Publications by authors named "Daqing Sun"

43 Publications

Inflammatory Indicators and Hematological Indices in Contrast-Induced Nephropathy Among Patients Receiving Coronary Intervention: A Systematic Review and Meta-Analysis.

Angiology 2021 Mar 15:33197211000492. Epub 2021 Mar 15.

Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.

Strong inflammatory indicators such as C-reactive protein (CRP), high-sensitivity CRP (hsCRP), and hematological indices, including platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), hematocrit (HCT), and red blood cell distribution width (RDW), may be related with contrast-induced nephropathy (CIN). Our meta-analysis aimed at exploring the relationship between these indicators and CIN incidence among patients undergoing coronary intervention. Clinical studies were retrieved from the electronic databases of PubMed, EMBASE, Google Scholar, Clinical Trials, and Science Direct from their inception to June 3, 2020. Meta-analysis was performed on pooled eligible studies. Finally, 26 studies involving 29 454 patients were included. Pooled analysis revealed that patients with higher CRP (odds ratio [OR] = 1.06, 95% CI: 1.01-1.12, = .02), hsCRP (OR = 1.03, 95% CI: 1.01-1.06, = .004), NLR (OR = 1.11, 95% CI: 1.01-1.20, = .02), RDW (OR = 1.35, 95% CI: 1.19-1.53, < .001), and lower HCT (OR = 0.94, 95% CI: 0.92-0.97, = .003) all exhibited significantly higher CIN rates, but there was no significant association between PLR and CIN risk (OR = 1.12, 95% CI: 0.99-1.26, = .07). Pre-angiography CRP/hsCRP and some hematological indices are associated with CIN.
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http://dx.doi.org/10.1177/00033197211000492DOI Listing
March 2021

Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production.

J Med Chem 2020 09 9;63(18):10433-10459. Epub 2020 Sep 9.

ORIC Pharmaceuticals, 240 E. Grand Avenue, Floor 2, South San Francisco, California 94080, United States.

The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5'-(α,β-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 () proved to be a highly potent and orally bioavailable CD73 inhibitor. In preclinical studies, completely inhibited ADO production in both human cancer cells and CD8 T cells. Furthermore, lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an tool compound for further development.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01086DOI Listing
September 2020

Cdc14a has a role in spermatogenesis, sperm maturation and male fertility.

Exp Cell Res 2020 10 15;395(1):112178. Epub 2020 Jul 15.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, 250100, PR China. Electronic address:

Cdc14a is an evolutionarily conserved dual-specific protein phosphatase, and it plays different roles in different organisms. Cdc14a mutations in human have been reported to cause male infertility, while the specific role of Cdc14a in regulation of the male reproductive system remains elusive. In the present study, we established a knockout mouse model to study the function of Cdc14a in male reproductive system. Cdc14a male mice were subfertile and they could only produce very few offspring. The number of sperm was decreased, the sperm motility was impaired, and the proportion of sperm with abnormal morphology was elevated in Cdc14a mice. When we mated Cdc14a male mice with wild-type (WT) female mice, fertilized eggs could be found in female fallopian tubes, however, the majority of these embryos died during development. Some empty spaces were observed in seminiferous tubule of Cdc14a testes. Compared with WT male mice, the proportions of pachytene spermatocytes were increased and germ cells stained with γH2ax were decreased in Cdc14a male mice, indicating that knockout of Cdc14a inhibited meiotic initiation. Subsequently, we analyzed the expression levels of some substrate proteins of Cdc14a, including Cdc25a, Wee1, and PR-Set7, and compared those with WT testes, in which the expression levels of these proteins were significantly increased in Cdc14a testes. Our results revealed that Cdc14a male mice are highly subfertile, and Cdc14a is essential for normal spermatogenesis and sperm function.
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http://dx.doi.org/10.1016/j.yexcr.2020.112178DOI Listing
October 2020

Precise annotation of human, chimpanzee, rhesus macaque and mouse mitochondrial genomes leads to insight into mitochondrial transcription in mammals.

RNA Biol 2020 03 10;17(3):395-402. Epub 2020 Jan 10.

College of Life Sciences, Nankai University, Tianjin, P.R.China.

In the present study, we applied our 'precise annotation' to the mitochondrial (mt) genomes of human, chimpanzee, rhesus macaque and mouse using 5' and 3' end small RNAs. Our new annotations updated previous annotations. In particular, our new annotations led to two important novel findings: (1) the identification of five Conserved Sequence Blocks (CSB1, CSB2, CSB3, LSP and HSP) in the control regions; and (2) the annotation of Transcription Initiation and novel Transcription Termination Sites. Based on these annotations, we proposed a novel model of mt transcription which can account for the mt transcription and its regulation in mammals. According to our model, Transcription Termination Sites function as switches to regulate the production of short, long primary transcripts and uninterrupted transcription, rather than simply terminate the mt transcription. Moreover, the expression levels of mitochondrial transcription termination factors control the proportions of rRNAs, mRNAs and lncRNAs in total mt RNA. Our findings point to the existence of many other, as yet unidentified, Transcription Termination Sites in mammals.
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http://dx.doi.org/10.1080/15476286.2019.1709746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999622PMC
March 2020

Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.

J Med Chem 2019 11 18;62(22):10258-10271. Epub 2019 Nov 18.

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of , a potent Mcl-1 inhibitor (IC = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01310DOI Listing
November 2019

Genome, transcriptome and fermentation analyses of Lactobacillus plantarum LY-78 provide new insights into the mechanism of phenyllactate biosynthesis in lactic acid bacteria.

Biochem Biophys Res Commun 2019 11 9;519(2):351-357. Epub 2019 Sep 9.

College of Food Science, Northeast Agricultural University, No. 600 Changjiang Road, Harbin, 150030, China. Electronic address:

Phenyllactate (PLA) is found in a variety of fermented foods and is a promising antibacterial agent, drug and plastic synthetic precursor. Previous studies have shown that PLA is a product of Phe catabolism in lactic acid bacteria (LAB), and PLA biosynthesis is mainly related to lactate dehydrogenases (LDHs). Here, the genome, transcriptome and fermentation characteristics of PLA-producing Lactobacillus plantarum LY-78 were studied. The fermentation experiments demonstrated that L. plantarum LY-78 possesses the ability to synthesize PLA de novo. Secondly, the genome and transcriptome analyses revealed candidate pathways, operons and key genes for PLA biosynthesis in the strain. Finally, genome-wide transcriptome analysis revealed significant changes in the expression profile of strain LY-78 in the absence and presence of PPA. Overall, this work demonstrates for the first time that PLA can be a by-product of Phe anabolism in LAB, provides new insights and evidence for elucidating the mechanism of PLA biosynthesis in LAB, and may provide new candidate genes and research strategies for future PLA biosynthesis applications.
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http://dx.doi.org/10.1016/j.bbrc.2019.09.011DOI Listing
November 2019

Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633).

J Med Chem 2019 07 5;62(14):6751-6764. Epub 2019 Jul 5.

ORIC Pharmaceuticals , 240 E. Grand Avenue, Fl2 , South San Francisco , California 94080 , United States.

Structure-based modification of mifepristone () led to the discovery of novel mifepristone derivatives with improved selectivity profile. Addition of a methyl group at the C10 position of the steroid has a significant impact on progesterone receptor (PR) and androgen receptor (AR) activity. Within this series, OP-3633 () emerged as a glucocorticoid receptor (GR) antagonist with increased selectivity against PR and AR, improved cytochrome P450 inhibition profile, and significantly improved pharmacokinetic properties compared to . Furthermore, demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00711DOI Listing
July 2019

A knock-in mouse model of Pendred syndrome with Slc26a4 L236P mutation.

Biochem Biophys Res Commun 2019 07 30;515(2):359-365. Epub 2019 May 30.

Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China. Electronic address:

SLC26A4 gene mutations lead to Pendred syndrome and non-syndromic hearing loss (DFNB4). The mouse model is well used to study the pathology of Pendred syndrome, however, mice with different Slc26a4 mutations exhibit different phenotypes, and these mice have severe deafness and inner ear malformations that are not imitated less severely Human phenotype. In this study, we generated a knock-in mouse model of Pendred syndrome with Slc26a4 L236P mutation to mimic the most common mutation found in human. Some L236P mice were observed to have significant vestibular dysfunction including torticollis and circling, the giant otoconia and destruction of the otoconial membrane was observed in L236P mice. Unlike other profoundly deafness in Slc26a4 mouse model, L236P mice present mild to profound hearing loss, consistent with the hearing threshold, inner ear hair cells also lost from slight to significant. Together, these data demonstrate that the L236P mouse phenotype is more similar to the human phenotype and should be used as a tool for further research into the human Pendred syndrome.
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http://dx.doi.org/10.1016/j.bbrc.2019.05.157DOI Listing
July 2019

Vanillic acid mitigates the ovalbumin (OVA)-induced asthma in rat model through prevention of airway inflammation.

Biosci Biotechnol Biochem 2019 Mar 13;83(3):531-537. Epub 2018 Nov 13.

b Department of Pediatric , Xi'An NO.3 Hospital , Xi'an , Shaanxi Province , China.

Asthma is a chronic allergic ailment affecting a considerably large population of the world. The aim of this study is to evaluate the ameliorative effects of vanillic acid against ovalbumin (OVA)-induced asthma in rat model. Asthma was induced in Sprague Dawley rats and vanillic acid was orally administered at 25 and 50 mg/kg body weight for 28 days. Rats challenged with OVA showed heavy signs of airway inflammation and remodeling similar to chronic asthma, evidenced by the increased differential cell counts and presence of inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), along with elevated serum immunoglobulin levels, and the histological results. However, vanillic acid dose-dependently attenuated the manifestation of OVA-induced asthma (p < 0.05) through suppression of inflammatory mediators and modulation of immunoglobulin levels in rats. The asthma mitigating properties of vanillic acid might be due to suppression of oxidative stress and prevention of lung airway inflammation.
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http://dx.doi.org/10.1080/09168451.2018.1543015DOI Listing
March 2019

Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101).

J Med Chem 2018 09 23;61(17):7767-7784. Epub 2018 Aug 23.

ORIC Pharmaceuticals , 240 East Grand Avenue, Fl2 , South San Francisco , California 94080 , United States.

The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00743DOI Listing
September 2018

Inhibition of NLRP9b attenuates acute lung injury through suppressing inflammation, apoptosis and oxidative stress in murine and cell models.

Biochem Biophys Res Commun 2018 09 29;503(2):436-443. Epub 2018 Jun 29.

Department of Pediatric, Xi'an NO.3 Hospital, Xi'an, Shaanxi 710018, China. Electronic address:

Acute lung injury (ALI), known a severe disease along with high morbidity and mortality, is lacking of specific therapies. Inflammation, apoptosis and oxidative stress are critical pathologies that contribute to ALI. Recently, there is study indicated that NLRP9b, a NOD-like receptor (NLR) member, is critical in modulation of inflammatory response. However, the effects of NLRP9b on sepsis-associated ALI, and the underlying molecular mechanism have not been understood. In the present study, the wild type (WT) and NLRP9b-knockout (NLRP9b) mice with C57B/L6 background were subjected to a cecal ligation and puncture (CLP) for ALI murine model establishment. The findings indicated that NLRP9b improved the survival rate of CLP-induced ALI mice, and inhibited pulmonary histopathological alterations, inflammation, and apoptosis. NLRP9b reduced the activation of inhibitor of κBα/nuclear factor kappa B (IκBα/NF-κB), apoptosis-associated speck-like protein containing a Caspase-recruitment domain (ASC)/Casapse-1 and Caspase-3/poly (ADP-ribose) polymerase (PARP) signaling pathways in CLP-challenged mice with ALI. In vitro, mouse epithelial cells (MLE-12) were incubated with lipopolysaccharide (LPS) or recombinant NLRP9b caused a significant increased of pro-inflammatory cytokines or chemokine, and reactive oxygen species (ROS) generation; however, these changes were markedly alleviated by NLRP9-knockdown using its specific siRNA sequence. Pre-treatment of MLE-12 cells with ROS scavenger of N-acetylcysteine (NAC) remarkably decreased lipopolysaccharide (LPS)- and rMuNLRP9-induced production of ROS, and the secretion of inflammatory cytokines or chemokine, as well as the activity of IκBα/NF-κB, ASC/Casapse-1 and Caspase-3/PARP signaling pathways. Together, the findings here suggested that NLRP9b played an essential role in lung inflammation, apoptosis and oxidative stress of sepsis-induced ALI animal model or in LPS-induced MLE-12 cells, providing that NLRP9b inhibition might be a potential therapeutic option for ALI.
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http://dx.doi.org/10.1016/j.bbrc.2018.04.079DOI Listing
September 2018

Transcription factor E2F1 promotes EMT by regulating ZEB2 in small cell lung cancer.

BMC Cancer 2017 Nov 7;17(1):719. Epub 2017 Nov 7.

Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, 264003, China.

Background: Epithelial-mesenchymal transition (EMT) is an early event in tumour invasion and metastasis, and widespread and distant metastasis at early stages is the typical biological behaviour in small cell lung cancer (SCLC). Our previous reports showed that high expression of the transcription factor E2F1 was involved in the invasion and metastasis of SCLC, but the role of E2F1 in the process of EMT in SCLC is unknown.

Methods: Immunohistochemistry was performed to evaluate the expressions of EMT related markers. Immunofluorescence was used to detect the expressions of cytoskeletal proteins and EMT related markers when E2F1 was silenced in SCLC cell lines. Adenovirus containing shRNA against E2F1 was used to knock down the E2F1 expression, and the dual luciferase reporter system was employed to clarify the regulatory relationship between E2F1 and ZEB2.

Results: In this study, we observed the remodelling of cytoskeletal proteins when E2F1 was silenced in SCLC cell lines, indicating that E2F1 was involved in the EMT in SCLC. Depletion of E2F1 promoted the expression of epithelial markers (CDH1 and CTNNB1) and inhibited the expression of mesenchymal markers (VIM and CDH2) in SCLC cell lines, verifying that E2F1 promotes EMT occurrence. Next, the mechanism by which E2F1 promoted EMT was explored. Among the CDH1 related inhibitory transcriptional regulators ZEB1, ZEB2, SNAI1 and SNAI2, the expression of ZEB2 was the highest in SCLC tissue samples and was highly consistent with E2F1 expression. ChIP-seq data and dual luciferase reporter system analysis confirmed that E2F1 could regulate ZEB2 gene expression.

Conclusion: Our data supports that E2F1 promotes EMT by regulating ZEB2 gene expression in SCLC.
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http://dx.doi.org/10.1186/s12885-017-3701-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678576PMC
November 2017

Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice.

Biochem Biophys Res Commun 2016 08 7;477(1):83-90. Epub 2016 Jun 7.

Department of Quality Control, Xi'an Children's Hospital, Xi'an 710003, PR China. Electronic address:

Unlabelled: Matrine has been demonstrated to attenuate allergic airway inflammation. Elevated suppressor of cytokine signaling 3 (SOCS3) was correlated with the severity of asthma. The aim of this study was to investigate the effect of matrine on SOCS3 expression in airway inflammation. In this study, we found that matrine significantly inhibited OVA-induced AHR, inflammatory cell infiltration, goblet cell differentiation, and mucous production in a dose-dependent manner in mice. Matrine also abrogated the level of interleukin (IL)-4 and IL-13, but enhanced interferon (IFN)-γ expression, both in BALF and in lung homogenates. Furthermore, matrine impeded TNF-α-induced the expression of IL-6 and adhesion molecules in airway epithelial cells (BEAS-2B and MLE-12). Additionally, we found that matrine inhibited SOCS3 expression, both in asthmatic mice and TNF-α-stimulated epithelial cells via suppression of the NF-κB signaling pathway by using pcDNA3.1-SOCS3 plasmid, SOCS3 siRNA, or nuclear factor kappa-B (NF-κB) inhibitor PDTC.

Conclusions: Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice.
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http://dx.doi.org/10.1016/j.bbrc.2016.06.024DOI Listing
August 2016

Epigallocatechin-3-gallate Protects against Hydrogen Peroxide-Induced Inhibition of Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells.

Stem Cells Int 2016 9;2016:7532798. Epub 2016 Feb 9.

Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.

Oxidative stress induces bone loss and osteoporosis, and epigallocatechin-3-gallate (EGCG) may be used to combat these diseases due to its antioxidative property. Herein, oxidative stress in human bone marrow-derived mesenchymal stem cells (BM-MSCs) was induced by H2O2, resulting in an adverse effect on their osteogenic differentiation. However, this H2O2-induced adverse effect was nullified when the cells were treated with EGCG. In addition, treatment of BM-MSCs with EGCG alone also resulted in the enhancement of osteogenic differentiation of BM-MSCs. After EGCG treatment, expressions of β-catenin and cyclin D1 were upregulated, suggesting that the Wnt pathway was involved in the effects of EGCG on the osteogenic differentiation of BM-MSCs. This was also confirmed by the fact that the Wnt pathway inhibitor, Dickkopf-1 (DKK-1), can nullify the EGCG-induced enhancement effect on BM-MSC's osteogenic differentiation. Hence, our results suggested that EGCG can reduce the effects of oxidative stress on Wnt pathway in osteogenic cells, which supported a potentially promising therapy of bone disorders induced by oxidative stress. Considering its positive effects on BM-MSCs, EGCG may also be beneficial for stem cell-based bone repair.
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http://dx.doi.org/10.1155/2016/7532798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763004PMC
March 2016

KatG and KatE confer Acinetobacter resistance to hydrogen peroxide but sensitize bacteria to killing by phagocytic respiratory burst.

Life Sci 2016 Mar 6;148:31-40. Epub 2016 Feb 6.

Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA. Electronic address:

Aims: Catalase catalyzes the degradation of H2O2. Acinetobacter species have four predicted catalase genes, katA, katE, katG, and katX. The aims of the present study seek to determine which catalase(s) plays a predominant role in determining the resistance to H2O2, and to assess the role of catalase in Acinetobacter virulence.

Main Methods: Mutants of Acinetobacter baumannii and Acinetobacter nosocomialis with deficiencies in katA, katE, katG, and katX were tested for sensitivity to H2O2, either by halo assays or by liquid culture assays. Respiratory burst of neutrophils, in response to A. nosocomialis, was assessed by chemiluminescence to examine the effects of catalase on the production of reactive oxygen species (ROS) in neutrophils. Bacterial virulence was assessed using a Galleria mellonella larva infection model.

Key Findings: The capacities of A. baumannii and A. nosocomialis to degrade H2O2 are largely dependent on katE. The resistance of both A. baumannii and A. nosocomialis to H2O2 is primarily determined by the katG gene, although katE also plays a minor role in H2O2 resistance. Bacteria lacking both the katG and katE genes exhibit the highest sensitivity to H2O2. While A. nosocomialis bacteria with katE and/or katG were able to decrease ROS production by neutrophils, these cells also induced a more robust respiratory burst in neutrophils than did cells deficient in both katE and katG. We also found that A. nosocomialis deficient in both katE and katG was more virulent than the wildtype A. nosocomialis strain.

Significance: Our findings suggest that inhibition of Acinetobacter catalase may help to overcome the resistance of Acinetobacter species to microbicidal H2O2 and facilitate bacterial disinfection.
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http://dx.doi.org/10.1016/j.lfs.2016.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792659PMC
March 2016

Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4.

Bioorg Med Chem Lett 2015 Dec 23;25(23):5546-50. Epub 2015 Oct 23.

Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

In this Letter, we report the continued optimization of the N-acyl-2-aminobenzimidazole series, focusing in particular on the N-alkyl substituent and 5-position of the benzimidazole based on the binding mode and the early SAR. These efforts led to the discovery of 16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4.
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http://dx.doi.org/10.1016/j.bmcl.2015.10.060DOI Listing
December 2015

Bone morphogenetic protein 2 regulates the differentiation of nitrergic enteric neurons by modulating Smad1 signaling in slow transit constipation.

Mol Med Rep 2015 Nov 7;12(5):6547-54. Epub 2015 Sep 7.

Department of General Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor superfamily and have been implicated in chondrogenesis and neuronal differentiation. In order to examine the function of bone morphogenetic protein 2 (BMP‑2) on the differentiation of nitrergic enteric neurons in slow transit constipation (STC), the expression of BMP‑2 and neuronal nitric oxide synthase (nNOS) was investigated in the myenteric nerve plexus in STC and control tissues by immunohistochemical assays. The present study demonstrated that BMP‑2 and nNOS were expressed in the myenteric nerve plexus and their levels were differentially altered in the STC group and control group. In addition, the effect of BMP‑2 on primary myenteric neurons was investigated by measuring the neurite length. The results demonstrated that BMP‑2 regulated the differentiation of primary enteric neurons and increased the length of neurites compared with the control group. In addition, the effect of BMP‑2 on the expression of nNOS was also investigated in primary enteric neurons and the Smad1 signal transduction pathway by western blot analysis, reverse transcription quantitative polymerase chain reaction and immunofluorescence assay. The results suggested that BMP‑2 promoted the expression of nNOS in primary myenteric neurons and induced phosphorylation of Smad1. These data indicate a new role for BMP‑2 as an important transcriptional cofactor that regulates the differentiation of nitrergic enteric neurons through the Smad1 pathway. Intervention of BMP‑2 may be useful for the treatment of STC.
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http://dx.doi.org/10.3892/mmr.2015.4297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626182PMC
November 2015

Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation.

Xenobiotica 2015 23;45(8):681-92. Epub 2015 Mar 23.

Department of Pharmacokinetics and Drug Metabolism and.

1. AMG 232 is a novel inhibitor of the p53-MDM2 protein-protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data. 2. AMG 232 exhibited low clearance (<0.25 × Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%). 3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered (14)C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species. 4. The in vitro-in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.
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http://dx.doi.org/10.3109/00498254.2015.1010632DOI Listing
April 2016

Synthesis, in Vitro Covalent Binding Evaluation, and Metabolism of (14)C-Labeled Inhibitors of 11β-HSD1.

ACS Med Chem Lett 2014 Nov 23;5(11):1245-50. Epub 2014 Sep 23.

Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.

In this letter, we reported the design and synthesis of three potent, selective, and orally bioavailable 11β-HSD1 inhibitors labeled with (14)C: AMG 456 (1), AM-6949 (2), and AM-7715 (3). We evaluated the covalent protein binding of the labeled inhibitors in human liver microsomes in vitro and assessed their potential bioactivation risk in humans. We then studied the in vitro mechanism of 2 in human hepatocytes and the formation of reactive intermediates. Our study results suggest that 1 and 3 have low potential for metabolic bioactivation in humans, while 2 has relatively high risk.
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http://dx.doi.org/10.1021/ml500331yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233368PMC
November 2014

Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction.

J Med Chem 2014 Dec 4;57(24):10499-511. Epub 2014 Dec 4.

Department of Therapeutic Discovery, ‡Department of Pharmaceutics, and §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.

Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.
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http://dx.doi.org/10.1021/jm501550pDOI Listing
December 2014

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.

ACS Med Chem Lett 2014 Aug 30;5(8):894-9. Epub 2014 Jun 30.

Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.

Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.
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http://dx.doi.org/10.1021/ml500142bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137378PMC
August 2014

Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction.

Bioorg Med Chem Lett 2014 Aug 1;24(16):3782-5. Epub 2014 Jul 1.

Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
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http://dx.doi.org/10.1016/j.bmcl.2014.06.073DOI Listing
August 2014

Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer.

J Med Chem 2014 Aug 9;57(15):6332-41. Epub 2014 Jul 9.

Department of Therapeutic Discovery, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.

We recently reported the discovery of AMG 232 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 protein-protein interaction. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer. This article provides an overview of its discovery from the de novo design of the piperidinone series to the structure-activity studies leading to the identification of 1. In addition, this article also describes the preclinical pharmacology and pharmacokinetics of 1, along with its drug metabolism and safety assessment.
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http://dx.doi.org/10.1021/jm500627sDOI Listing
August 2014

Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres.

J Med Chem 2014 Apr 27;57(7):2963-88. Epub 2014 Mar 27.

Departments of Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.

We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
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http://dx.doi.org/10.1021/jm401911vDOI Listing
April 2014

Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction.

J Med Chem 2014 Mar 4;57(6):2472-88. Epub 2014 Mar 4.

Departments of †Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.

We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
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http://dx.doi.org/10.1021/jm401767kDOI Listing
March 2014

Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development.

J Med Chem 2014 Feb 5;57(4):1454-72. Epub 2014 Feb 5.

Departments of Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California, 94080, United States.

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
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http://dx.doi.org/10.1021/jm401753eDOI Listing
February 2014

[Alterations in intestinal microflora balance induce maturity and increase the expressions of TLR2 and TLR4 of dendritic cells in mouse lung].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2013 Sep;29(9):923-6

Department of Clinical Immunology, Chongqing Medical University, Chongqing, China.

Objective: To observe the effect of intestinal microflora imbalance caused by antibiotics on the maturity of dendritic cells (DCs) and the expressions of Toll-like receptor 2 (TLR2), TLR4 on DCs in the lung of ovalbumin (OVA)-induced asthma mice.

Methods: Sixty-four 3-week-old female BALB/c mice were divided randomly into 4 groups, i.e. microbiota imbalance group, microbiota imbalamce combined with OVA challenge group, OVA challenge group and control group, with sixteen mice in each group. On day 14, flow cytometry was adopted to measure the DC subtypes and maturity (MHC-II molecules), and the expressions of TLR2, TLR4 on DCs. The expressions of transforming growth factor-β1 (TGF-β1) and interleukin-6 (IL-6) in situ in lung were detected by immunohistochemical staining. The levels of TGF-β1 and IL-6 in bronchoalveolar lavage fluid (BALF) were examined by ELISA.

Results: Compared with control group and OVA challenge group, MHC-II molecules and TLR2, TLR4 expressions on DCs in the lung increased in both microbiota imbalance combined with OVA challenge group and microbiota imbalance group, but they were not significantly different between the two groups (P>0.05). Compared with the other three groups, microbiota imbalance combined with OVA challenge group showed the up-regulated expressions of TGF-β1 and IL-6 proteins in lung and BALF.

Conclusion: The alterations in intestinal microflora balance promoted the maturity of DCs and raised the expressions of TLR2 and TLR4 on DCs in mouse lung.
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September 2013

Rational design and binding mode duality of MDM2-p53 inhibitors.

J Med Chem 2013 May 6;56(10):4053-70. Epub 2013 May 6.

Department of Therapeutic Discovery, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, USA.

Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.
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http://dx.doi.org/10.1021/jm400293zDOI Listing
May 2013

Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors.

Bioorg Med Chem Lett 2012 Jun 9;22(11):3786-90. Epub 2012 Apr 9.

Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).
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http://dx.doi.org/10.1016/j.bmcl.2012.04.005DOI Listing
June 2012

Structure-based design of novel inhibitors of the MDM2-p53 interaction.

J Med Chem 2012 Jun 9;55(11):4936-54. Epub 2012 May 9.

Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.

Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.
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http://dx.doi.org/10.1021/jm300354jDOI Listing
June 2012