Publications by authors named "Patrick T Flaherty"

21 Publications

  • Page 1 of 1

Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer.

Oncoscience 2021 18;8:64-71. Epub 2021 May 18.

Department of Medicine, Division of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA.

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options. A defining feature of TNBC is the propensity to metastasize and acquire resistance to cytotoxic agents. Mitogen activated protein kinase (MAPK) and extracellular regulated kinase (ERK) signaling pathways have integral roles in cancer development and progression. While MEK5/ERK5 signaling drives mesenchymal and migratory cell phenotypes in breast cancer, the specific mechanisms underlying these actions remain under-characterized. To elucidate the mechanisms through which MEK5 regulates the mesenchymal and migratory phenotype, we generated stably transfected constitutively active MEK5 (MEK5-ca) TNBC cells. Downstream signaling pathways and candidate targets of MEK5-ca cells were based on RNA sequencing and confirmed using qPCR and Western blot analyses. MEK5 activation drove a mesenchymal cell phenotype independent of cell proliferation effects. Transwell migration assays demonstrated MEK5 activation significantly increased breast cancer cell migration. In this study, we provide supporting evidence that MEK5 functions through FRA-1 to regulate the mesenchymal and migratory phenotype in TNBC.
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http://dx.doi.org/10.18632/oncoscience.535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131078PMC
May 2021

Crystal structure of -butyl 4-[4-(4-fluoro-phen-yl)-2-methyl-but-3-yn-2-yl]piperazine-1-carboxyl-ate.

Acta Crystallogr E Crystallogr Commun 2021 Apr 5;77(Pt 4):360-365. Epub 2021 Mar 5.

Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Ave, Pittsburgh, PA 15282, USA.

The title sterically congested piperazine derivative, CHFNO, was prepared using a modified Bruylants approach. A search of the Cambridge Structural Database identified 51 compounds possessing an butyl piperazine substructure. Of these only 14 were asymmetrically substituted on the piperazine ring and none with a synthetically useful second nitro-gen. Given the novel chemistry generating a pharmacologically useful core, determination of the crystal structure for this compound was necessary. The piperazine ring is present in a chair conformation with di-equatorial substitution. Of the two N atoms, one is hybridized while the other is hybridized. Inter-molecular inter-actions resulting from the crystal packing patterns were investigated using Hirshfeld surface analysis and fingerprint analysis. Directional weak hydrogen-bond-like inter-actions (C-H⋯O) and C-H⋯π inter-actions with the dispersion inter-actions as the major source of attraction are present in the crystal packing.
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http://dx.doi.org/10.1107/S2056989021002346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025862PMC
April 2021

Dual inhibition of MEK1/2 and MEK5 suppresses the EMT/migration axis in triple-negative breast cancer through FRA-1 regulation.

J Cell Biochem 2021 Apr 20. Epub 2021 Apr 20.

Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, Louisiana, USA.

Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan-MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.
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http://dx.doi.org/10.1002/jcb.29916DOI Listing
April 2021

Diverse and converging roles of ERK1/2 and ERK5 pathways on mesenchymal to epithelial transition in breast cancer.

Transl Oncol 2021 Jun 21;14(6):101046. Epub 2021 Mar 21.

Department of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA 15219, USA. Electronic address:

The epithelial to mesenchymal transition (EMT) is characterized by a loss of cell polarity, a decrease in the epithelial cell marker E-cadherin, and an increase in mesenchymal markers including the zinc-finger E-box binding homeobox (ZEB1). The EMT is also associated with an increase in cell migration and anchorage-independent growth. Induction of a reversal of the EMT, a mesenchymal to epithelial transition (MET), is an emerging strategy being explored to attenuate the metastatic potential of aggressive cancer types, such as triple-negative breast cancers (TNBCs) and tamoxifen-resistant (TAMR) ER-positive breast cancers, which have a mesenchymal phenotype. Patients with these aggressive cancers have poor prognoses, quick relapse, and resistance to most chemotherapeutic drugs. Overexpression of extracellular signal-regulated kinase (ERK) 1/2 and ERK5 is associated with poor patient survival in breast cancer. Moreover, TNBC and tamoxifen resistant cancers are unresponsive to most targeted clinical therapies and there is a dire need for alternative therapies. In the current study, we found that MAPK3, MAPK1, and MAPK7 gene expression correlated with EMT markers and poor overall survival in breast cancer patients using publicly available datasets. The effect of ERK1/2 and ERK5 pathway inhibition on MET was evaluated in MDA-MB-231, BT-549 TNBC cells, and tamoxifen-resistant MCF-7 breast cancer cells. Moreover, TU-BcX-4IC patient-derived primary TNBC cells were included to enhance the translational relevance of our study. We evaluated the effect of pharmacological inhibitors and lentivirus-induced activation or inhibition of the MEK1/2-ERK1/2 and MEK5-ERK5 pathways on cell morphology, E-cadherin, vimentin and ZEB1 expression. Additionally, the effects of pharmacological inhibition of trametinib and XMD8-92 on nuclear localization of ERK1/2 and ERK5, cell migration, proliferation, and spheroid formation were evaluated. Novel compounds that target the MEK1/2 and MEK5 pathways were used in combination with the AKT inhibitor ipatasertib to understand cell-specific responses to kinase inhibition. The results from this study will aid in the design of innovative therapeutic strategies that target cancer metastases.
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http://dx.doi.org/10.1016/j.tranon.2021.101046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020482PMC
June 2021

Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling.

Biomolecules 2021 01 29;11(2). Epub 2021 Jan 29.

Department of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, USA.

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.
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http://dx.doi.org/10.3390/biom11020183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911413PMC
January 2021

ERK5 Is Required for Tumor Growth and Maintenance Through Regulation of the Extracellular Matrix in Triple Negative Breast Cancer.

Front Oncol 2020 3;10:1164. Epub 2020 Aug 3.

Section of Hematology & Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States.

Conventional mitogen-activated protein kinase (MAPK) family members regulate diverse cellular processes involved in tumor initiation and progression, yet the role of ERK5 in cancer biology is not fully understood. Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. ERK5 signaling contributes to drug resistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT). More recently a role for ERK5 in regulation of the extracellular matrix (ECM) has been proposed, and here we investigated the necessity of ERK5 in TNBC tumor formation. Depletion of ERK5 expression using the CRISPR/Cas9 system in MDA-MB-231 and Hs-578T cells resulted in loss of mesenchymal features, as observed through gene expression profile and cell morphology, and suppressed TNBC cell migration. xenograft experiments revealed ERK5 knockout disrupted tumor growth kinetics, which was restored using high concentration Matrigel™ and ERK5-ko reduced expression of the angiogenesis marker CD31. These findings implicated a role for ERK5 in the extracellular matrix (ECM) and matrix integrity. RNA-sequencing analyses demonstrated downregulation of matrix-associated genes, integrins, and pro-angiogenic factors in ERK5-ko cells. Tissue decellularization combined with cryo-SEM and interrogation of biomechanical properties revealed that ERK5-ko resulted in loss of key ECM fiber alignment and mechanosensing capabilities in breast cancer xenografts compared to parental wild-type cells. In this study, we identified a novel role for ERK5 in tumor growth kinetics through modulation of the ECM and angiogenesis axis in breast cancer.
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http://dx.doi.org/10.3389/fonc.2020.01164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416559PMC
August 2020

Pharmacological inhibition of the MEK5/ERK5 and PI3K/Akt signaling pathways synergistically reduces viability in triple-negative breast cancer.

J Cell Biochem 2020 02 28;121(2):1156-1168. Epub 2019 Aug 28.

Department of Pharmacology and Toxicology, Duquesne University, Pittsburgh, Pennsylvania.

Triple-negative breast cancers (TNBCs) represent 15% to 20% of all breast cancers and are often associated with poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Aberrations in the phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. While the crosstalk between PI3K and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways has been characterized in several systems, new evidence suggests that MEK5/ERK5 signaling is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/protein kinase B (Akt) and MEK5/ERK5 in the MDA-MB-231, BT-549, and MDA-MB-468 TNBC cell lines. We used the Akt inhibitor ipatasertib, ERK5 inhibitors XMD8-92 and AX15836, and the novel MEK5 inhibitor SC-1-181 to investigate the effects of dual inhibition. Our results indicated that dual inhibition of PI3K/Akt and MEK5/ERK5 signaling was more effective at reducing the proliferation and survival of TNBCs than single inhibition of either pathway alone. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. In addition, the dual inhibition strategy was determined to be synergistic in MDA-MB-231 and BT-549 cells and was relatively nontoxic in the nonneoplastic MCF-10 cell line. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs.
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http://dx.doi.org/10.1002/jcb.29350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923606PMC
February 2020

Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer.

Front Oncol 2019 30;9:672. Epub 2019 Jul 30.

Division of Medicinal Chemistry, School of Pharmacy, Duquesne University, Pittsburgh, PA, United States.

Epithelial to mesenchymal transition (EMT) is a cellular program that converts non-motile epithelial cells into invasive mesenchymal cells. EMT is implicated in cancer metastasis, chemo-resistance, cancer progression, and generation of cancer stem cells (CSCs). Inducing mesenchymal to epithelial transition (MET), the reverse phenomenon of EMT, is proposed as a novel strategy to target triple negative and tamoxifen-resistant breast cancer. Triple negative breast cancer (TNBC) is characterized by the loss of hormone receptors, a highly invasive mesenchymal phenotype, and a lack of targeted therapy. Estrogen receptor-positive breast cancer can be targeted by tamoxifen, an ER antagonist. However, these cells undergo EMT over the course of treatment and develop resistance. Thus, there is an urgent need to develop therapeutic interventions to target these aggressive cancers. In this study, we examined the role of novel diphenylamine analogs in converting the mesenchymal phenotype of MDA-MB-231 TNBC cells to a lesser aggressive epithelial phenotype. Using analog-based drug design, a series of diphenylamine analogs were synthesized and initially evaluated for their effect on E-cadherin protein expression and changes incell morphology, which was quantified by measuring the spindle index (SI) value. Selected compound from this series increases the expression of E-cadherin, a primary marker for epithelial cells, and decreases the mesenchymal markers SOX2, ZEB1, Snail, and vimentin. The increase in epithelial markers and the decrease in mesenchymal markers are consistent with a phenotypic switch from spindle-like morphology to cobblestone-like morphology. Furthermore, Compound decreases spheroid viability, cell migration, and cell proliferation in triple negative BT-549 and tamoxifen-resistant MCF-7 breast cancer cells.
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http://dx.doi.org/10.3389/fonc.2019.00672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682674PMC
July 2019

Structure activity relationships of anthranilic acid-based compounds on cellular and in vivo mitogen activated protein kinase-5 signaling pathways.

Bioorg Med Chem Lett 2018 07 20;28(13):2294-2301. Epub 2018 May 20.

Department of Pharmacology, School of Pharmacy, Duquesne University, 410A Mellon Hall, 600 Forbes Ave., Pittsburgh, PA 15282, United States.

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http://dx.doi.org/10.1016/j.bmcl.2018.05.029DOI Listing
July 2018

-Acetyl-l-Cysteine Protects Astrocytes against Proteotoxicity without Recourse to Glutathione.

Mol Pharmacol 2017 11 22;92(5):564-575. Epub 2017 Aug 22.

Division of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (A.M.G., D.F.H., T.N.B., L.C.L., P.T.F., R.K.L.); and Departments of Biological Sciences (S.S., J.L.B.) and Chemistry and Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W.)

-acetyl-l-cysteine (NAC) exhibits protective properties in brain injury models and has undergone a number of clinical trials. Most studies of NAC have focused on neurons. However, neuroprotection may be complemented by the protection of astrocytes because healthier astrocytes can better support the viability of neurons. Here, we show that NAC can protect astrocytes against protein misfolding stress (proteotoxicity), the hallmark of neurodegenerative disorders. Although NAC is thought to be a glutathione precursor, NAC protected primary astrocytes from the toxicity of the proteasome inhibitor MG132 without eliciting any increase in glutathione. Furthermore, glutathione depletion failed to attenuate the protective effects of NAC. MG132 elicited a robust increase in the folding chaperone heat shock protein 70 (Hsp70), and NAC mitigated this effect. Nevertheless, three independent inhibitors of Hsp70 function ablated the protective effects of NAC, suggesting that NAC may help preserve Hsp70 chaperone activity and improve protein quality control without need for Hsp70 induction. Consistent with this view, NAC abolished an increase in ubiquitinated proteins in MG132-treated astrocytes. However, NAC did not affect the loss of proteasome activity in response to MG132, demonstrating that it boosted protein homeostasis and cell viability without directly interfering with the efficacy of this proteasome inhibitor. The thiol-containing molecules l-cysteine and d-cysteine both mimicked the protective effects of NAC, whereas the thiol-lacking molecule -acetyl--methyl-l-cysteine failed to exert protection or blunt the rise in ubiquitinated proteins. Collectively, these findings suggest that the thiol group in NAC is required for its effects on glial viability and protein quality control.
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http://dx.doi.org/10.1124/mol.117.109926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635514PMC
November 2017

Oncogenic signaling of MEK5-ERK5.

Cancer Lett 2017 04 30;392:51-59. Epub 2017 Jan 30.

Department of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, USA; Department of Pharmacology, Tulane University, New Orleans, LA, USA; Tulane Cancer Center, Tulane University, New Orleans, LA, USA. Electronic address:

Mitogen-activated protein kinases (MAPKs) regulate diverse cellular processes including proliferation, cell survival, differentiation, and apoptosis. While conventional MAPK constituents have well-defined roles in oncogenesis, the MEK5 pathway has only recently emerged in cancer research. In this review, we consider the MEK5 signaling cascade, focusing specifically on its involvement in drug resistance and regulation of aggressive cancer phenotypes. Moreover, we explore the role of MEK5/ERK5 in tumorigenesis and metastatic progression, discussing the discrepancies in preclinical studies and assessing its viability as a therapeutic target for anti-cancer agents.
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http://dx.doi.org/10.1016/j.canlet.2017.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901897PMC
April 2017

Identification of HIV inhibitors guided by free energy perturbation calculations.

Curr Pharm Des 2012 ;18(9):1199-216

Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849, USA.

Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605731PMC
http://dx.doi.org/10.2174/138161212799436421DOI Listing
July 2012

Biphenyl/diphenyl ether renin inhibitors: filling the S1 pocket of renin via the S3 pocket.

Bioorg Med Chem Lett 2011 Aug 17;21(16):4836-43. Epub 2011 Jun 17.

Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA.

Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.
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http://dx.doi.org/10.1016/j.bmcl.2011.06.043DOI Listing
August 2011

Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25.

Bioorg Med Chem 2011 Jan 6;19(1):359-73. Epub 2010 Dec 6.

Department of Medicinal Chemistry, Mylan School of Pharmacy, Duquesne University, 600 Forbes Hall, Pittsburgh, PA 15282, USA.

Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in cognitive and behavioral impairment. The two classic pathological hallmarks of AD include extraneuronal deposition of amyloid β (Aβ) and intraneuronal formation of neurofibrillary tangles (NFTs). NFTs contain hyperphosphorylated tau. Tau is the major microtubule-associated protein in neurons and stabilizes microtubules (MTs). Cyclin dependent kinase 5 (CDK5), when activated by the regulatory binding protein p25, phosphorylates tau at a number of proline-directed serine/threonine residues, resulting in formation of phosphorylated tau as paired helical filaments (PHFs) then in subsequent deposition of PHFs as NFTs. Beginning with the structure of Roscovitine, a moderately selective CDK5 inhibitor, we sought to conduct structural modifications to increase inhibitory potency of CDK5 and increase selectivity over a similar enzyme, cyclin dependent kinase 2 (CDK2). The design, synthesis, and testing of a series of 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles is presented.
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http://dx.doi.org/10.1016/j.bmc.2010.11.022DOI Listing
January 2011

Structure-activity relationships of benzimidazole-based selective inhibitors of the mitogen activated kinase-5 signaling pathway.

Bioorg Med Chem 2010 Nov 19;18(22):8054-60. Epub 2010 Oct 19.

Division of Medicinal Chemistry, School of Pharmacy, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15282, United States.

In a prior communication we identified a novel class of benzimidazole-based inhibitors of EGF-induced phosphorylation of ERK5. In this paper we examine the biological activity of several 1-isopropyl-4-amino-6-ether linked benzimidazole-based compounds for their ability to selectively inhibit EGF-mediated ERK5 phosphorylation; potential utility of variation at the 6-position was indicated by the initial structural feature survey. Modification of EGF-induced formation of pERK1/2 and pERK5 in HEK293 cells were analyzed by Western blot analysis. Subsequent analysis of selected compounds in a high-throughput multiple kinase scan and the NCI 60-cell-line screen is presented.
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http://dx.doi.org/10.1016/j.bmc.2010.09.017DOI Listing
November 2010

Identification of benzimidazole-based inhibitors of the mitogen activated kinase-5 signaling pathway.

Bioorg Med Chem Lett 2010 May 10;20(9):2892-6. Epub 2010 Mar 10.

Division of Medicinal Chemistry, School of Pharmacy, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15282, USA.

The MEK-signaling pathways are complex but critical signaling cascades that correlate an extracellular signaling event with internal cell processes. To date at least seven MEK isozymes have been identified. MEK5, in particular, is upregulated in multiple forms of tumors. Analysis of the EGF-induced MEK5 signaling cascade in cultured HEK cells has identified compounds that can inhibit MEK5 phosphorylation of ERK5; observed biological activity is dependent on chemical variation.
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http://dx.doi.org/10.1016/j.bmcl.2010.03.033DOI Listing
May 2010

Optimization of orally bioavailable alkyl amine renin inhibitors.

Bioorg Med Chem Lett 2010 Jan 1;20(2):694-9. Epub 2009 Dec 1.

Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA.

Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
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http://dx.doi.org/10.1016/j.bmcl.2009.11.066DOI Listing
January 2010

Design and optimization of renin inhibitors: Orally bioavailable alkyl amines.

Bioorg Med Chem Lett 2009 Jul 5;19(13):3541-5. Epub 2009 May 5.

Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA.

Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
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http://dx.doi.org/10.1016/j.bmcl.2009.04.140DOI Listing
July 2009

1-Isopropyl-4-nitro-6-meth-oxy-1H-benzimidazole.

Acta Crystallogr Sect E Struct Rep Online 2008 Jun 25;64(Pt 7):o1336-7. Epub 2008 Jun 25.

Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.

There are two independent mol-ecules in the asymmetric unit of the title compound, C(11)H(13)N(3)O(3). The inter-planar angles for the two rings of the benzimidazole ring system is 2.21 (12)° in one mol-ecule and 0.72 (12)° in the other. The nitro group is twisted in the same direction relative to the least-squares plane through its attached benzene ring in both mol-ecules, with inter-planar angles of 15.22 (9) and 18.02 (8)°. In the crystal structure, mol-ecules are stacked along the a axis through π-π inter-actions (centroid-centroid distance 4.1954 Å). C-H⋯O hydrogen bonds are also present.
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http://dx.doi.org/10.1107/S160053680801859XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2961682PMC
June 2008

Synthesis and anti-tubulin activity of a 3'-(4-azidophenyl)-3'-dephenylpaclitaxel photoaffinity probe.

J Med Chem 2004 Dec;47(26):6459-65

Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, USA.

The synthesis and biological evaluation of a novel paclitaxel photoaffinity probe is described. The synthesis involved the preparation of an azide-containing C13 side chain through a Staudinger cycloaddition followed by a lipase-mediated kinetic resolution to obtain the azetidinone in 99% ee. Coupling of the enantiopure side chain precursor to 7-TES-baccatin III and subsequent silyl ether deprotection afforded 3'-(4-azidophenyl)-3'-dephenylpaclitaxel, which was shown to be as active as paclitaxel in tubulin assembly and cytotoxicity assays.
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http://dx.doi.org/10.1021/jm030581dDOI Listing
December 2004

Formal total synthesis of (+)-salicylihalamides A and B: a combined chiral pool and RCM strategy.

J Org Chem 2003 Dec;68(26):10030-9

Department of Medicinal Chemistry, Center for Cancer Experimental Therapeutics, and the Drug Discovery Program, Higuchi Biosciences Center, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, USA.

The formal total synthesis of the (+)-salicylihalamides A and B is detailed, utilizing a chiral pool approach to generate the three stereogenic centers and a ring-closing metathesis (RCM) for the formation of the macrocyclic ring structure. Starting from a known glucose-derived alcohol, the formal total synthesis was achieved in an efficient 13-step protocol in 26% overall yield. It was found that substitution at the remote phenolic group significantly influenced the ratio of the E- and Z-double bond products in the RCM step. The introduction of phenol protecting groups provided E-isomers preferentially and also enhanced the rates of the RCM reactions.
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http://dx.doi.org/10.1021/jo0301550DOI Listing
December 2003