Publications by authors named "Noelle S Williams"

65 Publications

Reducing acetylated tau is neuroprotective in brain injury.

Cell 2021 May 13;184(10):2715-2732.e23. Epub 2021 Apr 13.

Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH, USA.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.
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http://dx.doi.org/10.1016/j.cell.2021.03.032DOI Listing
May 2021

Maternal P7C3-A20 Treatment Protects Offspring from Neuropsychiatric Sequelae of Prenatal Stress.

Antioxid Redox Signal 2021 Jan 29. Epub 2021 Jan 29.

Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.

Impaired embryonic cortical interneuron development from prenatal stress is linked to adult neuropsychiatric impairment, stemming in part from excessive generation of reactive oxygen species in the developing embryo. Unfortunately, there are no preventive medicines that mitigate the risk of prenatal stress to the embryo, as the underlying pathophysiologic mechanisms are poorly understood. Our goal was to interrogate the molecular basis of prenatal stress-mediated damage to the embryonic brain to identify a neuroprotective strategy. Chronic prenatal stress in mice dysregulated nicotinamide adenine dinucleotide (NAD) synthesis enzymes and cortical interneuron development in the embryonic brain, leading to axonal degeneration in the hippocampus, cognitive deficits, and depression-like behavior in adulthood. Offspring were protected from these deleterious effects by concurrent maternal administration of the NAD-modulating agent P7C3-A20, which crossed the placenta to access the embryonic brain. Prenatal stress also produced axonal degeneration in the adult corpus callosum, which was not prevented by maternal P7C3-A20. Prenatal stress dysregulates gene expression of NAD-synthesis machinery and GABAergic interneuron development in the embryonic brain, which is associated with adult cognitive impairment and depression-like behavior. We establish a maternally directed treatment that protects offspring from these effects of prenatal stress. NAD-synthesis machinery and GABAergic interneuron development are critical to proper embryonic brain development underlying postnatal neuropsychiatric functioning, and these systems are highly susceptible to prenatal stress. Pharmacologic stabilization of NAD in the stressed embryonic brain may provide a neuroprotective strategy that preserves normal embryonic development and protects offspring from neuropsychiatric impairment.
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http://dx.doi.org/10.1089/ars.2020.8227DOI Listing
January 2021

Loss of wild type KRAS in KRAS lung adenocarcinoma is associated with cancer mortality and confers sensitivity to FASN inhibitors.

Lung Cancer 2021 03 2;153:73-80. Epub 2021 Jan 2.

Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, 75390, United States. Electronic address:

Objectives: Wild type RAS (RAS) suppresses the function of oncogenic RAS mutants (RAS) in laboratory models. Loss of RAS, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RAS cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RAS cancers is attractive as a potential biomarker for targeted therapy.

Materials And Methods: We evaluated for associations between LAKR and cancer mortality in patients with KRAS lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRAS LAKR, including combination strategies involving clinical KRAS and FASN inhibitors.

Results: 24 % of patients with KRAS LUAD showed LAKR. KRAS LAKR cases had a median survival of 16 vs. 30 months in KRAS non-LAKR (p =  0.017) and LAKR was independently associated with death in this cohort (p =  0.011). We also found that KRAS LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRAS LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRAS inhibitor MRTX849 in LUAD cells with KRAS and LAKR, including an in vivo trial using a xenograft model.

Conclusions: LAKR in KRAS cancers may represent an independent negative prognostic factor for patients with KRAS LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRAS and FASN inhibitors in patients with KRAS LAKR is warranted.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897317PMC
March 2021

Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity.

J Med Chem 2021 01 14;64(2):1139-1169. Epub 2021 Jan 14.

Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215, United States.

The essential eukaryotic chaperone Hsp90 regulates the form and function of diverse client proteins, many of which govern thermotolerance, virulence, and drug resistance in fungal species. However, use of Hsp90 inhibitors as antifungal therapeutics has been precluded by human host toxicities and suppression of immune responses. We recently described resorcylate aminopyrazoles (RAPs) as the first class of Hsp90 inhibitors capable of discriminating between fungal (, ) and human isoforms of Hsp90 in biochemical assays. Here, we report an iterative structure-property optimization toward RAPs capable of inhibiting growth in culture. In addition, we report the first X-ray crystal structures of Hsp90 nucleotide binding domain (NBD), as the apoprotein and in complexes with the non-species-selective Hsp90 inhibitor NVP-AUY922 and three RAPs revealing unique ligand-induced conformational rearrangements, which reaffirm the hypothesis that intrinsic differences in protein flexibility can confer selective inhibition of fungal versus human Hsp90 isoforms.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01777DOI Listing
January 2021

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris.

Nat Commun 2020 12 22;11(1):6429. Epub 2020 Dec 22.

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.
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http://dx.doi.org/10.1038/s41467-020-20183-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755909PMC
December 2020

Assessing the safety of transarterial locoregional delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat liver.

Eur J Pharm Biopharm 2021 Jan 24;158:273-283. Epub 2020 Nov 24.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Internal Medicine Division of Liver and Digestive Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Electronic address:

Hepatic-arterial infusion (HAI) of low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) (LDL-DHA) has been shown in a rat hepatoma model to be a promising treatment for hepatocellular carcinoma. To date, little is known regarding the safety of HAI of LDL-DHA to the liver. Therefore, we aimed to investigate the deposition, metabolism and safety of HAI of LDL-DHA (2, 4 or 8 mg/kg) in the rat. Following HAI, fluorescent labeled LDL nanoparticles displayed a biexponential plasma concentration time curve as the particles were rapidly extracted by the liver. Overall, increasing doses of HAI of LDL-DHA was well tolerated in the rat. Body weight, plasma biochemistry and histology were all unremarkable and molecular markers of inflammation did not increase with treatment. Lipidomics analyses showed that LDL-DHA was preferentially oxidized to the anti-inflammatory mediator, protectin DX. We conclude that HAI of LDL-DHA nanoparticles is not only safe, but provides potential hepatoprotective benefits.
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http://dx.doi.org/10.1016/j.ejpb.2020.10.018DOI Listing
January 2021

Inhibition of the de novo pyrimidine biosynthesis pathway limits ribosomal RNA transcription causing nucleolar stress in glioblastoma cells.

PLoS Genet 2020 11 17;16(11):e1009117. Epub 2020 Nov 17.

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

Glioblastoma is the most common and aggressive type of cancer in the brain; its poor prognosis is often marked by reoccurrence due to resistance to the chemotherapeutic agent temozolomide, which is triggered by an increase in the expression of DNA repair enzymes such as MGMT. The poor prognosis and limited therapeutic options led to studies targeted at understanding specific vulnerabilities of glioblastoma cells. Metabolic adaptations leading to increased synthesis of nucleotides by de novo biosynthesis pathways are emerging as key alterations driving glioblastoma growth. In this study, we show that enzymes necessary for the de novo biosynthesis of pyrimidines, DHODH and UMPS, are elevated in high grade gliomas and in glioblastoma cell lines. We demonstrate that DHODH's activity is necessary to maintain ribosomal DNA transcription (rDNA). Pharmacological inhibition of DHODH with the specific inhibitors brequinar or ML390 effectively depleted the pool of pyrimidines in glioblastoma cells grown in vitro and in vivo and impaired rDNA transcription, leading to nucleolar stress. Nucleolar stress was visualized by the aberrant redistribution of the transcription factor UBF and the nucleolar organizer nucleophosmin 1 (NPM1), as well as the stabilization of the transcription factor p53. Moreover, DHODH inhibition decreased the proliferation of glioblastoma cells, including temozolomide-resistant cells. Importantly, the addition of exogenous uridine, which reconstitutes the cellular pool of pyrimidine by the salvage pathway, to the culture media recovered the impaired rDNA transcription, nucleolar morphology, p53 levels, and proliferation of glioblastoma cells caused by the DHODH inhibitors. Our in vivo data indicate that while inhibition of DHODH caused a dramatic reduction in pyrimidines in tumor cells, it did not affect the overall pyrimidine levels in normal brain and liver tissues, suggesting that pyrimidine production by the salvage pathway may play an important role in maintaining these nucleotides in normal cells. Our study demonstrates that glioblastoma cells heavily rely on the de novo pyrimidine biosynthesis pathway to generate ribosomal RNA (rRNA) and thus, we identified an approach to inhibit ribosome production and consequently the proliferation of glioblastoma cells through the specific inhibition of the de novo pyrimidine biosynthesis pathway.
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http://dx.doi.org/10.1371/journal.pgen.1009117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707548PMC
November 2020

Functional imaging of RAS pathway targeting in malignant peripheral nerve sheath tumor cells and xenografts.

Pediatr Blood Cancer 2020 12 25;67(12):e28639. Epub 2020 Sep 25.

Department of Pediatrics Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.

Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive form of soft-tissue sarcoma (STS) in children. Despite intensive therapy, relatively few children with metastatic and unresectable disease survive beyond three years. RAS pathway activation is common in MPNST, suggesting MEK pathway inhibition as a targeted therapy, but the impact on clinical outcome has been small to date.

Procedure: We conducted preclinical pharmacokinetic (PK) and pharmacodynamic studies of two MEK inhibitors, trametinib and selumetinib, in two MPNST models and analyzed tumors for intratumor drug levels. We then investigated 3'-deoxy-3'-[ F]fluorothymidine ( F-FLT) PET imaging followed by F-FDG PET/CT imaging of MPNST xenografts coupled to short-term or longer-term treatment with selumetinib focusing on PET-based imaging as a biomarker of MEK inhibition.

Results: Trametinib decreased pERK expression in MPNST xenografts but did not prolong survival or decrease Ki67 expression. In contrast, selumetinib prolonged survival of animals bearing MPNST xenografts, and this correlated with decreased pERK and Ki67 staining. PK studies revealed a significantly higher fraction of unbound selumetinib within a responsive MPNST xenograft model. Thymidine uptake, assessed by F-FLT PET/CT, positively correlated with Ki67 expression in different xenograft models and in response to selumetinib.

Conclusion: The ability of MEK inhibitors to control MPNST growth cannot simply be predicted by serum drug levels or drug-induced changes in pERK expression. Tumor cell proliferation assessed by F-FLT PET imaging might be useful as an early response marker to targeted therapies, including MEK inhibition, where a primary effect is cell-cycle arrest.
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http://dx.doi.org/10.1002/pbc.28639DOI Listing
December 2020

The effect of injected dose on localized tumor accumulation and cardiac uptake of doxorubicin in a Vx2 rabbit tumor model using MR-HIFU mild hyperthermia and thermosensitive liposomes.

Int J Hyperthermia 2020 ;37(1):1052-1059

Department of Radiology, UT Southwestern Medical Center, Dallas, TX, USA.

Purpose: When doxorubicin (DOX) is administered lyso-thermosensitive liposomes (LTLD), mild hyperthermia enhances localized delivery to heated vs. unheated tumors. The optimal LTLD dose and the impact of different doses on systemic drug distribution are unknown.

In this study, we evaluated local and systemic DOX delivery with three LTLD doses (0.1, 0.5, and 2.5 mg/kg) in a Vx2 rabbit tumor model. Temporally and spatially accurate controlled hyperthermia was achieved using a clinical MR-HIFU system for the intended heating duration (40 min).

DOX concentration in tissues delivered from LTLD combined with MR-HIFU mild hyperthermia are dose-dependent, including heated/unheated tumor, heart, and other healthy organs. Higher DOX accumulation and tumor-to-heart drug concentration ratio, defined as the ratio of DOX delivered into the tumor vs the heart, were observed in heated tumors compared to unheated tumors in all three tested doses. The DOX uptake efficiency for each mg/kg of LTLD injected IV of heated tumor was significantly higher than that of unheated tumor and heart within the tested dose range (0.1-2.5 mg/kg). The DOX uptake for the heart linearly scaled up as a function of dose while that for the heated tumor showed some evidence of saturation at the high dose of 2.5 mg/kg.

These results provide guidance on clinical protocol design of hyperthermia-triggered drug delivery.
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http://dx.doi.org/10.1080/02656736.2020.1812737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727403PMC
January 2020

Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase.

J Med Chem 2020 09 19;63(17):9773-9786. Epub 2020 Aug 19.

Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9038, United States.

A series of -acyl benzothiazoles shows selective and potent cytotoxicity against cancer cell lines expressing cytochrome P450 4F11. A prodrug form is metabolized by cancer cells into an active inhibitor of stearoyl-CoA desaturase (SCD). Substantial variation on the acyl portion of the inhibitors allowed the identification of ()-, which balanced potency, solubility, and lipophilicity to allow proof-of-concept studies in mice. The prodrugs were activated inside the tumor, where they can arrest tumor growth. Together, these observations offer promise that a tumor-activated prodrug strategy might exploit the essentiality of SCD for tumor growth, while avoiding toxicity associated with systemic SCD inhibition.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00899DOI Listing
September 2020

Benzothiourea Derivatives Target the Secretory Pathway of the Human Fungal Pathogen .

ACS Infect Dis 2020 03 26;6(3):529-539. Epub 2020 Feb 26.

Department of Pediatrics, Carver College of Medicine, University of Iowa, 25 South Grand Avenue, Iowa City, Iowa 52245, United States.

is one of the most important human fungal pathogens and causes life-threatening meningoencephalitis in immunocompromised patients. The current gold standard therapy for meningoencephalitis is based on medications that are over 50 years old and is not readily available in regions with high disease burden. Here, we report the mycologic, mechanistic, and pharmacologic characterization of a set of benzothioureas with highly selective fungicidal activity against . In addition, to direct antifungal activity, benzothioureas inhibit virulence traits. On the basis of a set of phenotypic, biochemical, and biophysical assays, the benzothioureas (BTUs) inhibit the late secretory pathway (post-Golgi), possibly through a direct interaction with Sav1, an orthologue of the Sec4-class small GTPase. Importantly, pharmacological characterization of the BTUs indicates it readily penetrates the blood-brain barrier. Together, our data support the further development of this scaffold as an antifungal agent with a novel mechanism of action against .
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http://dx.doi.org/10.1021/acsinfecdis.9b00478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664160PMC
March 2020

MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer.

Genes Dev 2019 09 15;33(17-18):1236-1251. Epub 2019 Aug 15.

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Tumors display increased uptake and processing of nutrients to fulfill the demands of rapidly proliferating cancer cells. Seminal studies have shown that the proto-oncogene MYC promotes metabolic reprogramming by altering glutamine uptake and metabolism in cancer cells. How MYC regulates the metabolism of other amino acids in cancer is not fully understood. Using high-performance liquid chromatography (HPLC)-tandem mass spectrometry (LC-MS/MS), we found that MYC increased intracellular levels of tryptophan and tryptophan metabolites in the kynurenine pathway. MYC induced the expression of the tryptophan transporters SLC7A5 and SLC1A5 and the enzyme arylformamidase (AFMID), involved in the conversion of tryptophan into kynurenine. SLC7A5, SLC1A5, and AFMID were elevated in colon cancer cells and tissues, and kynurenine was significantly greater in tumor samples than in the respective adjacent normal tissue from patients with colon cancer. Compared with normal human colonic epithelial cells, colon cancer cells were more sensitive to the depletion of tryptophan. Blocking enzymes in the kynurenine pathway caused preferential death of established colon cancer cells and transformed colonic organoids. We found that only kynurenine and no other tryptophan metabolite promotes the nuclear translocation of the transcription factor aryl hydrocarbon receptor (AHR). Blocking the interaction between AHR and kynurenine with CH223191 reduced the proliferation of colon cancer cells. Therefore, we propose that limiting cellular kynurenine or its downstream targets could present a new strategy to reduce the proliferation of MYC-dependent cancer cells.
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http://dx.doi.org/10.1101/gad.327056.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719621PMC
September 2019

Design and Synthesis of TASIN Analogues Specifically Targeting Colorectal Cancer Cell Lines with Mutant Adenomatous Polyposis Coli (APC).

J Med Chem 2019 05 9;62(10):5217-5241. Epub 2019 May 9.

Despite advances in targeted anticancer therapies, there are still no small-molecule-based therapies available that specifically target colorectal cancer (CRC) development and progression, the second leading cause of cancer deaths. We previously disclosed the discovery of truncating adenomatous polyposis coli (APC)-selective inhibitor 1 (TASIN-1), a small molecule that specifically targets colorectal cancer cells lines with truncating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene through inhibition of cholesterol biosynthesis. Here, we report a medicinal chemistry evaluation of a collection of TASIN analogues and activity against colon cancer cell lines and an isogenic cell line pair reporting on the status of APC-dependent selectivity. A number of potent and selective analogues were identified, including compounds with good metabolic stability and pharmacokinetic properties. The compounds reported herein represent a first-in-class genotype-selective series that specifically target apc mutations present in the majority of CRC patients and serve as a translational platform toward a targeted therapy for colon cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252524PMC
May 2019

NQO1-dependent, Tumor-selective Radiosensitization of Non-small Cell Lung Cancers.

Clin Cancer Res 2019 04 7;25(8):2601-2609. Epub 2019 Jan 7.

Department of Biochemistry and Molecular Biology, Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.

Purpose: Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLC) is urgently needed. Here, we investigated the ability of β-lapachone (β-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1-3 Gy) in NSCLCs that overexpress NAD(P)H:Quinone Oxidoreductase 1 (NQO1).

Experimental Design: The mechanism of lethality of low-dose IR in combination with sublethal doses of β-lap was evaluated in NSCLC lines and validated in subcutaneous and orthotopic xenograft models . Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus cotreatments were performed to validate therapeutic efficacy and mechanism of action.

Results: β-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD/ATP levels, and increased double-strand break (DSB) lesions over time . Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 β-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (∼12 units) of any normal tissue. PK/PD responses confirm that IR + β-lap treatments hyperactivate PARP activity, greatly lower NAD/ATP levels, and dramatically inhibit DSB repair in exposed NQO1 cancer tissue, whereas low NQO1 levels and high levels of catalase in associated normal tissue were protective.

Conclusions: Our data suggest that combination of sublethal doses of β-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + β-lap against patients with NQO1 NSCLCs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788754PMC
April 2019

Targeting NAD Metabolism to Enhance Radiation Therapy Responses.

Semin Radiat Oncol 2019 01;29(1):6-15

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.

Nicotinamide adenine dinucleotide (NAD) metabolism is integrally connected with the mechanisms of action of radiation therapy and is altered in many radiation-resistant tumors. This makes NAD metabolism an ideal target for therapies that increase radiation sensitivity and improve patient outcomes. This review provides an overview of NAD metabolism in the context of the cellular response to ionizing radiation, as well as current therapies that target NAD metabolism to enhance radiation therapy responses. Additionally, we summarize state-of-the-art methods for measuring, modeling, and manipulating NAD metabolism, which are being used to identify novel targets in the NAD metabolic network for therapeutic interventions in combination with radiation therapy.
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http://dx.doi.org/10.1016/j.semradonc.2018.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310039PMC
January 2019

Longer heating duration increases localized doxorubicin deposition and therapeutic index in Vx2 tumors using MR-HIFU mild hyperthermia and thermosensitive liposomal doxorubicin.

Int J Hyperthermia 2019 12;36(1):196-203. Epub 2018 Dec 12.

a Department of Radiology , UT Southwestern Medical Center , Dallas , TX , USA.

Thermosensitive liposomal doxorubicin (LTSL-Dox) combined with mild hyperthermia enhances the localized delivery of doxorubicin (Dox) within a heated region. The optimal heating duration and the impact of extended heating on systemic drug distribution are unknown. Here we evaluated local and systemic Dox delivery with two different mild hyperthermia durations (42 °C for 10 or 40 minutes) in a Vx2 rabbit tumor model. We hypothesized that longer duration of hyperthermia would increase Dox concentration in heated tumors without increasing systemic exposure. Temporally and spatially accurate controlled hyperthermia was achieved using a clinical MR-HIFU system for the prescribed heating durations. Forty-minutes of heating resulted in a nearly 6-fold increase in doxorubicin concentration in heated vs unheated tumors in the same animals. Therapeutic ratio, defined as the ratio of Dox delivered into the heated tumor vs the heart, increased from 1.9-fold with 10 minutes heating to 4.4-fold with 40 minutes heating. MR-HIFU can be used to guide, deliver and monitor mild hyperthermia of a Vx2 tumor model in a rabbit model, and an increased duration of heating leads to higher Dox deposition from LTSL-Dox in a target tumor without a concomitant increase in systemic exposure. Results from this preclinical study can be used to help establish clinical treatment protocols for hyperthermia mediated drug delivery.
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http://dx.doi.org/10.1080/02656736.2018.1550815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430695PMC
January 2020

Neuroprotective efficacy of P7C3 compounds in primate hippocampus.

Transl Psychiatry 2018 09 26;8(1):202. Epub 2018 Sep 26.

University Hospital Case Medical Center; Department of Psychiatry Case Western Reserve University; Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland VAMC, Harrington Discovery Institute, Cleveland, OH, 44106, USA.

There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions. Previously, a target-agnostic in vivo screen in mice identified P7C3 aminopropyl carbazole as capable of enhancing the net magnitude of postnatal neurogenesis by protecting young neurons from death. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. During weeks 2-11, monkeys received weekly injection of 5'-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. BrdU+ cells were quantified using unbiased stereology. Separately in mice, the proneurogenic efficacy of P7C3-A20 was compared to that of NSI-189, a proneurogenic drug currently in clinical trials for patients with major depression. Orally-administered P7C3-A20 provided sustained plasma exposure, was well-tolerated, and elevated the survival of hippocampal BrdU+ cells in nonhuman primates without adverse central or peripheral tissue effects. In mice, NSI-189 was shown to be pro-proliferative, and P7C3-A20 elevated the net magnitude of hippocampal neurogenesis to a greater degree than NSI-189 through its distinct mechanism of promoting neuronal survival. This pilot study provides evidence that P7C3-A20 safely protects neurons in nonhuman primates, suggesting that the neuroprotective efficacy of P7C3 compounds is likely to translate to humans as well.
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http://dx.doi.org/10.1038/s41398-018-0244-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158178PMC
September 2018

Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase.

J Med Chem 2018 06 19;61(12):5199-5221. Epub 2018 Jun 19.

Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and related N-acyl ureas and an analysis of the structure-activity relationships related to metabolic activation and SCD inhibition.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350083PMC
June 2018

Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.

Cell 2018 05 19;173(4):864-878.e29. Epub 2018 Apr 19.

Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.
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http://dx.doi.org/10.1016/j.cell.2018.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935540PMC
May 2018

Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells.

Sci Rep 2018 01 17;8(1):967. Epub 2018 Jan 17.

The Center for Drug Discovery, Design and Delivery, the Center for Scientific Computing, Southern Methodist University, Dallas, TX, 75275-0376, USA.

Overexpression of ATP-binding cassette (ABC) transporters is often linked to multidrug resistance (MDR) in cancer chemotherapies. P-glycoprotein (P-gp) is one of the best studied drug transporters associated with MDR. There are currently no approved drugs available for clinical use in cancer chemotherapies to reverse MDR by inhibiting P-glycoprotein. Using computational studies, we previously identified several compounds that inhibit P-gp by targeting its nucleotide binding domain and avoiding its drug binding domains. Several of these compounds showed successful MDR reversal when tested on a drug resistant prostate cancer cell line. Using conventional two-dimensional cell culture of MDR ovarian and prostate cancer cells and three dimensional prostate cancer microtumor spheroids, we demonstrated here that co-administration with chemotherapeutics significantly decreased cell viability and survival as well as cell motility. The P-gp inhibitors were not observed to be toxic on their own. The inhibitors increased cellular retention of chemotherapeutics and reporter compounds known to be transport substrates of P-gp. We also showed that these compounds are not transport substrates of P-gp and that two of the three inhibit P-gp, but not the closely related ABC transporter, ABCG2/BCRP. The results presented suggest that these P-gp inhibitors may be promising leads for future drug development.
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http://dx.doi.org/10.1038/s41598-018-19325-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772368PMC
January 2018

(-)-P7C3-S243 Protects a Rat Model of Alzheimer's Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia.

Biol Psychiatry 2018 10 6;84(7):488-498. Epub 2017 Nov 6.

Department of Psychiatry, Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Neurology, Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa; Free Radical and Radiation Biology Program, Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa; Pappajohn Biomedical Institute, Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa; Interdisciplinary Graduate Program in Human Toxicology, Department of Occupational and Environmental Health, University of Iowa College of Public Health, Iowa City, Iowa; Iowa City VA Health Care System, Iowa City, Iowa; Weill Cornell Autism Research Program, Weill Cornell Medical College New York, New York. Electronic address:

Background: In addition to cognitive deficits, Alzheimer's disease (AD) is associated with other neuropsychiatric symptoms, including severe depression. Indeed, depression often precedes cognitive deficits in patients with AD. Unfortunately, the field has seen only minimal therapeutic advances, underscoring the critical need for new treatments. P7C3 aminopropyl carbazoles promote neuronal survival by enhancing nicotinamide adenine dinucleotide flux in injured neurons. Neuroprotection with P7C3 compounds has been demonstrated in preclinical models of neurodegeneration by virtue of promoting neuronal survival independently of early disease-specific pathology, resulting in protection from cognitive deficits and depressive-like behavior. We hypothesize that P7C3 compounds might be uniquely applicable to patients with AD, given the comorbid presentation of depression and cognitive deficits.

Methods: Aging male and female wild-type and TgF344-AD rats, a well-characterized preclinical AD model, were administered (-)-P7C3-S243 daily for 9 and 18 months, beginning at 6 months of age. Behavioral phenotypes related to cognition and depression were assessed at 15 and 24 months, and brain pathology and biochemistry were assessed at 24 months.

Results: (-)-P7C3-S243 safely protected aging male and female wild-type and TgF344-AD rats from cognitive deficits and depressive-like behavior. Depressive-like behavior occurred earlier than cognitive deficits in TgF344-AD rats, consistent with AD in many patients. Treatment with (-)-P7C3-S243 blocked neurodegeneration in TgF344-AD rats, without altering amyloid deposition or indicators of neuroinflammation.

Conclusions: Neuronal cell death-specific treatment approaches, such as P7C3 compounds, may represent a new treatment approach for patients experiencing the combination of cognitive deficits and depression associated with AD.
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http://dx.doi.org/10.1016/j.biopsych.2017.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415524PMC
October 2018

Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma.

Cancer Discov 2017 08 28;7(8):832-851. Epub 2017 Apr 28.

Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas.

Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathologic activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathologic ERK1/2 signaling. By integration of multigenome chemical and genetic screens, recurrent architectural variants in melanoma tumor genomes, and patient outcome data, we identified two mechanistic subtypes of BRAF melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKε inhibitors. Importantly, subtype membership can be predicted using a robust quantitative five-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKε inhibitor-sensitive disease among nonresponders to current targeted therapy. This study identified two mechanistic subtypes of melanoma: (1) the best responders to clinical BRAF/MEK inhibitors (25%) and (2) nonresponders due to primary resistance mechanisms (9.9%). We identified robust biomarkers that can detect these subtypes in patient samples and predict clinical outcome. TBK1/IKBKε inhibitors were selectively toxic to drug-resistant melanoma. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-0955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540806PMC
August 2017

Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair.

J Med Chem 2017 05 25;60(9):3979-4001. Epub 2017 Apr 25.

Department of Biochemistry, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.

The enzyme 15-prostaglandin dehydrogenase (15-PGDH) catalyzes the first step in the degradation of prostaglandins including PGE2. It is a negative regulator of tissue repair and regeneration in multiple organs. Accordingly, inhibitors of 15-PGDH are anticipated to elevate in vivo levels of PGE2 and to promote healing and tissue regeneration. The small molecule SW033291 (1) inhibits 15-PGDH with K = 0.1 nM in vitro, doubles PGE2 levels in vivo, and shows efficacy in mouse models of recovery from bone marrow transplantation, ulcerative colitis, and partial hepatectomy. Here we describe optimized variants of 1 with improved solubility, druglike properties, and in vivo activity.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580352PMC
May 2017

Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion.

mBio 2017 04 4;8(2). Epub 2017 Apr 4.

Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA

Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication. Ebola virus and other emerging RNA viruses are significant but unpredictable public health threats. Therapeutic approaches with broad-spectrum activity could provide an attractive response to such infections. We describe a novel assay that can identify small molecules that overcome Ebola virus-encoded innate immune evasion mechanisms. This assay identified as hits cancer chemotherapeutic drugs, including doxorubicin. Follow-up studies provide new insight into how doxorubicin induces interferon (IFN) responses, revealing activation of both the DNA damage response kinase ATM and the DNA sensor cGAS and its partner signaling protein STING. The studies further demonstrate that the ATM and cGAS-STING pathways of IFN induction are a point of vulnerability not only for Ebola virus but for other RNA viruses as well, because viral innate immune antagonists consistently fail to block these signals. These studies thereby define a novel avenue for therapeutic intervention against emerging RNA viruses.
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http://dx.doi.org/10.1128/mBio.00368-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380843PMC
April 2017

Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study.

Lancet Infect Dis 2017 06 28;17(6):626-635. Epub 2017 Mar 28.

Medicines for Malaria Venture, Geneva, Switzerland. Electronic address:

Background: DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity.

Methods: Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2).

Findings: In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (C) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (t) between 1·5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1·55 (95% CI 1·42-1·67) and in the mefloquine (10 mg/kg) group was 2·34 (2·17-2·52), corresponding to a parasite clearance half-life of 9·4 h (8·7-10·2) and 6·2 h (5·7-6·7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552-1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0·0001).

Interpretation: The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment.

Funding: Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S1473-3099(17)30171-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446412PMC
June 2017

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.

Science 2017 04 16;356(6336). Epub 2017 Mar 16.

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity have so far been unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam's cytotoxicity. RBM39 associates with precursor messenger RNA (pre-mRNA) splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing. Many cancer cell lines derived from hematopoietic and lymphoid lineages are sensitive to indisulam, and their sensitivity correlates with DCAF15 expression levels. Two other clinically tested sulfonamides, tasisulam and chloroquinoxaline sulfonamide, share the same mechanism of action as indisulam. We propose that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs (splicing inhibitor sulfonamides).
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http://dx.doi.org/10.1126/science.aal3755DOI Listing
April 2017

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist.

Proc Natl Acad Sci U S A 2017 02 31;114(7):1649-1654. Epub 2017 Jan 31.

Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;

The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, , has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.
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http://dx.doi.org/10.1073/pnas.1621346114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320972PMC
February 2017

Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors.

J Med Chem 2017 02 31;60(3):1142-1150. Epub 2017 Jan 31.

Chemistry Center, National Institute of Biological Science , Beijing 102206, China.

Pyruvate dehydrogenase kinases 1-4 (PDK1-4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure, and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in 1 and 2 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor (S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)-4-oxobutanamide (17) shows a ∼8-fold lower IC (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides additional interactions with Glu-262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996997PMC
February 2017

Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.

Cancer Cell 2016 Dec;30(6):940-952

Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA. Electronic address:

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1 cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.
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http://dx.doi.org/10.1016/j.ccell.2016.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161231PMC
December 2016

Development of a triazole class of highly potent Porcn inhibitors.

Bioorg Med Chem Lett 2016 12 11;26(24):5891-5895. Epub 2016 Nov 11.

Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

The acyltransferase Porcupine (Porcn) is essential for the secretion of Wnt proteins which contribute to embryonic development, tissue regeneration, and tumorigenesis. We have previously discovered four molecular scaffolds harboring Porcn-inhibitory activity. Comparison of their structures led to the identification of a general scaffold that can be readily assembled by modular synthesis. We report herein the development of a triazole version of this new class of Porcn inhibitors. This study yielded IWP-O1, a Porcn inhibitor with an EC value of 80pM in a cultured cell reporter assay of Wnt signaling. Additionally, IWP-O1 has significantly improved metabolic stability over our previously reported Porcn inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2016.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142825PMC
December 2016