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Dive into the research topics where Liang Schweizer is active.

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Featured researches published by Liang Schweizer.


BMC Cell Biology | 2008

The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens

Liang Schweizer; Cheryl A. Rizzo; Thomas Spires; J. Suso Platero; Qiuyan Wu; Tai-An Lin; Marco M. Gottardis; Ricardo M. Attar

BackgroundA crucial event in Prostate Cancer progression is the conversion from a hormone-sensitive to a hormone-refractory disease state. Correlating with this transition, androgen receptor (AR) amplification and mutations are often observed in patients failing hormonal ablation therapies. β-Catenin, an essential component of the canonical Wnt signaling pathway, was shown to be a coactivator of the AR signaling in the presence of androgens. However, it is not yet clear what effect the increased levels of the AR could have on the Wnt signaling pathway in these hormone-refractory prostate cells.ResultsTransient transfections of several human prostate cancer cell lines with the AR and multiple components of the Wnt signaling pathway demonstrate that the AR overexpression can potentiate the transcriptional activities of Wnt/β-Catenin signaling. In addition, the simultaneous activation of the Wnt signaling pathway and overexpression of the AR promote prostate cancer cell growth and transformation at castration levels of androgens. Interestingly, the presence of physiological levels of androgen or other AR agonists inhibits these effects. These observations are consistent with the nuclear co-localization of the AR and β-Catenin shown by immunohistochemistry in human prostate cancer samples. Furthermore, chromatin immunoprecipitation assays showed that Wnt3A can recruit the AR to the promoter regions of Myc and Cyclin D1, which are well-characterized downstream targets of the Wnt signalling pathway. The same assays demonstrated that the AR and β-Catenin can be recruited to the promoter and enhancer regions of a known AR target gene PSA upon Wnt signaling. These results suggest that the AR is promoting Wnt signaling at the chromatin level.ConclusionOur findings suggest that the AR signaling through the Wnt/β-Catenin pathway should be added to the well established functional interactions between both pathways. Moreover, our data show that via this interaction the AR could promote prostate cell malignancy in a ligand-independent manner.


Cancer Research | 2009

Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer

Ricardo M. Attar; Maria Jure-Kunkel; Aaron Balog; Mary Ellen Cvijic; Janet Dell-John; Cheryl A. Rizzo; Liang Schweizer; Thomas Spires; J. Suso Platero; Mary T. Obermeier; Weifang Shan; Mark E. Salvati; William R. Foster; Joseph E. Dinchuk; Shen-Jue Chen; Gregory D. Vite; Robert Kramer; Marco M. Gottardis

Despite an excellent initial response to first-line hormonal treatment, most patients with metastatic prostate cancer will succumb to a hormone-refractory form of the disease. Because these tumors are still dependent on a functional androgen receptor (AR), there is a need to find novel and more potent antiandrogens. While searching for small molecules that bind to the AR and inhibit its transcriptional activity, BMS-641988 was discovered. This novel antiandrogen showed an increased (>1 log) potency compared with the standard antiandrogen, bicalutamide, in both binding affinity to the AR and inhibition of AR-mediated transactivation in cell-based reporter assays. In mature rats, BMS-641988 strongly inhibited androgen-dependent growth of the ventral prostate and seminal vesicles. In the CWR-22-BMSLD1 human prostate cancer xenograft model, BMS-641988 showed increased efficacy over bicalutamide (average percent tumor growth inhibition >90% versus <50%), even at exposure levels of bicalutamide 3-fold greater than what can be attained in humans. Furthermore, BMS-641988 was efficacious in CWR-22-BMSLD1 tumors initially refractory to treatment with bicalutamide. BMS-641988 was highly efficacious in the LuCaP 23.1 human prostate xenograft model, inducing stasis throughout the approximately 30-day dosing. To explore the functional mechanisms of BMS-641988, gene expression profiling analysis was done on CWR-22-BMSLD1 xenograft models in mice. Treatment with BMS-641988 resulted in a global gene expression profile more similar to castration compared with that of bicalutamide. Overall, these data highlight that the unique preclinical profile of BMS-641988 may provide additional understanding for the hormonal treatment of prostate cancer.


Annals of the New York Academy of Sciences | 2014

Targeting epigenetic regulators for cancer therapy

Susan Wee; Dash Dhanak; Haitao Li; Scott A. Armstrong; Robert A. Copeland; Robert Sims; Stephen B. Baylin; Xiaole Shirley Liu; Liang Schweizer

Human gene expression patterns are controlled and coordinated by the activity of a diverse array of epigenetic regulators, including histone methyltransferases, acetyltransferases, and chromatin remodelers. Deregulation of these epigenetic pathways can lead to genome‐wide changes in gene expression, with serious disease consequences. In recent years, research has suggested that cross talk between genomic (i.e., for example, mutations, translocations) and epigenomic factors may drive the etiology of both hematologic malignancies and solid tumors. Current work in translational research seeks to identify epigenetic regulators whose aberrant activity contributes to oncogenesis, including the histone methyltransferases DOT1L and EZH2 and the bromodomain‐containing BET family, and to develop drugs that inhibit the aberrant activity of these regulators. Preclinical and clinical studies using small‐molecule inhibitors of epigenetic regulators have underscored their value for therapeutic intervention, and these inhibitors can also be used to drive further studies into dissecting the functions of epigenetic factors in normal and cancer cells.


Molecular Cancer Therapeutics | 2015

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

Ryan Lenhart; Stefan Kirov; Heshani Desilva; Jian Cao; Ming Lei; Kathy A. Johnston; Russell Peterson; Liang Schweizer; Ashok V. Purandare; Petra Ross-Macdonald; Craig R. Fairchild; Tai W. Wong; Susan Wee

The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers, such as multiple myeloma. In this study, we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in downregulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need. Mol Cancer Ther; 14(10); 2167–74. ©2015 AACR.


ACS Medicinal Chemistry Letters | 2015

Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

Aaron Balog; Richard Rampulla; Gregory Scott Martin; Stanley R. Krystek; Ricardo M. Attar; Janet Dell-John; John D. Dimarco; David J. Fairfax; Jack Z. Gougoutas; Christian L. Holst; Andrew Nation; Cheryl A. Rizzo; Lana M. Rossiter; Liang Schweizer; Weifang Shan; Steven H. Spergel; Thomas Spires; Georgia Cornelius; Marco M. Gottardis; George L. Trainor; Gregory D. Vite; Mark E. Salvati

BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.


Current Chemical Genomics and Translational Medicine | 2014

Establishing a High-content Analysis Method for Tubulin Polymerizationto Evaluate Both the Stabilizing and Destabilizing Activities of Compounds

Chi Shing Sum; Debra Nickischer; Ming Lei; Andrea D. Weston; Litao Zhang; Liang Schweizer

Microtubules are important components of the cellular cytoskeleton that play roles in various cellular processes such as vesicular transport and spindle formation during mitosis. They are formed by an ordered organization of α-tubulin and β-tubulin hetero-polymers. Altering microtubule polymerization has been known to be the mechanism of action for a number of therapeutically important drugs including taxanes and epothilones. Traditional cell-based assays for tubulin-interacting compounds rely on their indirect effects on cell cycle and/or cell proliferation. Direct monitoring of compound effects on microtubules is required to dissect detailed mechanisms of action in a cellular setting. Here we report a high-content assay platform to monitor tubulin polymerization status by directly measuring the acute effects of drug candidates on the cellular tubulin network with the capability to dissect the mechanisms of action. This high-content analysis distinguishes in a quantitative manner between compounds that act as tubulin stabilizers versus those that are tubulin destabilizers. In addition, using a multiplex approach, we expanded this analysis to simultaneously monitor physiological cellular responses and associated cellular phenotypes.


Bioorganic & Medicinal Chemistry Letters | 2011

Arylsulfonamidopiperidone derivatives as a novel class of factor Xa inhibitors.

Yan Shi; Stephen P. O'connor; Doree Sitkoff; Jing Zhang; Mengxiao Shi; Sharon N. Bisaha; Ying Wang; Chi Li; Zheming Ruan; R. Michael Lawrence; Herbert E. Klei; Kevin Kish; Eddie C.-K. Liu; Steve M. Seiler; Liang Schweizer; Thomas E. Steinbacher; William A. Schumacher; Jeffrey A. Robl; John E. Macor; Karnail S. Atwal; Philip D. Stein

The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 μM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.


Bioorganic & Medicinal Chemistry Letters | 2010

Design and synthesis of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.02,6]undec-4-yl]-2-trifluoromethyl-benzonitriles as androgen receptor antagonists

Hai-Yun Xiao; Aaron Balog; Ricardo M. Attar; David J. Fairfax; Linda Fleming; Christian L. Holst; Gregory Scott Martin; Lana M. Rossiter; Jing Chen; Mary-Ellen Cvjic; Janet Dell-John; Jieping Geng; Marco M. Gottardis; Wen-Ching Han; Andrew Nation; Mary T. Obermeier; Cheryl A. Rizzo; Liang Schweizer; Thomas Spires; Weifang Shan; Ashvinikumar V. Gavai; Mark E. Salvati; Gregory D. Vite

A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo.


Journal of Biomolecular Screening | 2016

Development of a Human Whole Blood Screening Platform to Monitor JAK/STAT Signaling Using High-Throughput Flow Cytometry

Mark P. Fereshteh; Xin Li; Sha Li; Yi Fan; Rosemary Zhang; Glen A. Farr; Garrett Kolodin; Jonathan Lippy; Joseph G. Naglich; Gary L. Schieven; Liang Schweizer; Litao Zhang

Oral agents targeting Janus-associated kinases (JAKs) are promising new agents in clinical development. To better understand the relationship between JAK inhibition and biological outcome, compounds targeting JAKs were evaluated in peripheral human whole blood. To date, these analyses are low throughput and costly. Here, we developed a robust 384-well, high-throughput flow-based assay approach to screen small molecules for JAK/STAT signaling inhibition in human whole blood. This assay platform provides a highly sensitive analysis of signaling events in blood and facilitates measurement of target engagement. Further, the automation technologies and process optimizations developed here overcame sample integrity, handling, and multiparametric data analysis bottlenecks without affecting assay performance. Together these efforts dramatically increased sample throughput compared to conventional manual flow cytometric approaches and enabled development of novel JAK/STAT inhibitors.


Cancer Growth and Metastasis | 2013

enhancing cancer Drug Discovery through novel cell signaling pathway panel strategy

Liang Schweizer; Litao Zhang

The link between signaling pathways and diseases suggests the importance of pathway analysis for drug discovery. This includes target identification and validation, compound mode of action and drug candidate optimization. Here, we propose to apply cell signaling pathway panel approaches for oncology drug discovery. The strategies and guiding principles of the pathway panel approach are discussed. 2 pathway analysis examples with related processes and technology platforms are illustrated to identify cancer drugs that target cancer growth and metastasis. Finally, we highlight potential challenges and opportunities presented by the pathway panel approach.

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Ming Lei

Bristol-Myers Squibb

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