Article
Pathology
Xu Wang, Xiaolin Wei, Yu Cao, Peng Xing
Summary: Overexpression of ZNF33A in triple-negative breast cancer is associated with worse prognosis, promoting cell growth and resistance to BET inhibitors. ZNF33A also induces c-Myc, a key player in BET inhibitor resistance. Thus, inhibition of ZNF33A may enhance sensitivity of TNBC cells to BET inhibitors.
AMERICAN JOURNAL OF PATHOLOGY
(2022)
Article
Chemistry, Medicinal
Dan Wei, Hanlin Wang, Qinghe Zeng, Wenjing Wang, Bingbing Hao, Xule Feng, Peipei Wang, Ning Song, Weijuan Kan, Guifang Huang, Xiaoyu Zhou, Minjia Tan, Yubo Zhou, Ruimin Huang, Jia Li, Xiao-Hua Chen
Summary: TNBC is highly aggressive and clinically challenging due to limited treatment options. Targeting transcription-associated CDK9 with a novel degrader compound shows great promise in inhibiting TNBC cell growth and inducing apoptosis by downregulating transcriptional targets like MYC. This study establishes compound 45 as a potent and efficacious CDK9 degrader for potential targeted therapy in TNBC.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Maria Mushtaq Ali, Sehrish Naz, Sajda Ashraf, Stefan Knapp, Zaheer Ul-Haq
Summary: BRD9 inhibitors have potential therapeutic value in cancer treatment by selectively targeting BRD9 and BRD7 proteins, regulating chromatin structure and gene expression, and inhibiting tumor growth and progression.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Chemistry, Medicinal
Xuetao Chen, Fanying Meng, Jingtian Zhang, Zijian Zhang, Xuan Ye, Weikun Zhang, Yuanyuan Tong, Xinrui Ji, Rujun Xu, Xiao-Li Xu, Qi-Dong You, Zheng-Yu Jiang
Summary: Sepsis is a global health problem and BRD4 inhibitor 27 could be a potential candidate for sepsis treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Junhua Li, Run Zhu, Xiaoxi Zhuang, Cheng Zhang, Hui Shen, Xishan Wu, Maofeng Zhang, Cen Huang, Qiuping Xiang, Linxiang Zhao, Yong Xu, Yan Zhang
Summary: In this study, a class of novel BET bivalent inhibitors based on a monovalent BET inhibitor 7 (Y06037) was designed, optimized, and evaluated. The representative bivalent inhibitor 17b exhibited 32-fold greater potency in inhibiting cell growth in LNCaP compared to monovalent inhibitor 7. Furthermore, 17b induced 95.1% PSA regression in LNCaP cells at a concentration of 2 μM. Docking study revealed the potential binding mode of 17b with two BET bromodomains. These findings suggest that 17b (Y13021) is a promising BET bivalent inhibitor for the treatment of prostate cancer.
BIOORGANIC CHEMISTRY
(2023)
Article
Nutrition & Dietetics
Sabeeta Kapoor, Elisabetta Damiani, Shan Wang, Ravirajan Dharmanand, Chakrapani Tripathi, Jorge Enrique Tovar Perez, Wan Mohaiza Dashwood, Praveen Rajendran, Roderick Hugh Dashwood
Summary: Epigenetic mechanisms, specifically the deregulation of bromodomain (BRD) functions, play a significant role in colorectal cancer (CRC) and other malignancies. This study shows that overexpression of BRD9 is associated with poor prognostic outcomes in CRC patients. Natural polyphenols such as Epigallocatechin-3-gallate (EGCG), Equol, Quercetin, and Aspalathin were identified as potential BRD9 antagonists, as they reduced colon cancer cell viability, inhibited colony formation, and increased DNA damage and apoptosis.
Article
Biochemistry & Molecular Biology
Elisa Funck-Brentano, Dzeneta Vizlin-Hodzic, Jonas A. Nilsson, Lisa M. Nilsson
Summary: The study found that several MEK inhibitors can enhance apoptosis in response to HMBA in rat and human glioma cells in vitro as well as in vivo xenografts. This combination therapy has shown anti-cancer activities in multiple other tumor types but hasn't been successfully translated to the clinic.
Review
Chemistry, Medicinal
Dayu Wu, Qiong Duan
Summary: BET proteins play a key role in transcriptional regulation, particularly in metabolic processes such as adipogenesis and metaflammation. Recent studies have shown their involvement in diseases such as cancer and inflammation. This article discusses the latest research on BET proteins and their regulation of metabolism in cellular and animal models, and summarizes data from randomized clinical trials evaluating BET inhibitors for the treatment of metabolic diseases.
Article
Oncology
Chun-Shan Liu, Inmaculada Rioja, Ali Bakr, Marlon R. Veldwijk, Elena Sperk, Carsten Herskind, Dieter Weichenhan, Rab K. Prinjha, Christoph Plass, Peter Schmezer, Odilia Popanda
Summary: This study investigated the effects and toxicity of different inhibitors targeting BET proteins on radiation-induced fibroblast activation. The results showed that BD2-selective targeting inhibitors efficiently suppressed the expression of DGKA and profibrotic markers without showing cytotoxicity.
INTERNATIONAL JOURNAL OF CANCER
(2022)
Article
Chemistry, Medicinal
Jifa Zhang, Chengcan Yang, Pan Tang, Juncheng Chen, Dan Zhang, Yang Li, Gaoxia Yang, Yun Liu, Yiwen Zhang, Yuxi Wang, Jie Liu, Liang Ouyang
Summary: This study describes the development of a highly selective compound, BP44, targeting BRD4 and PARP1, which triggers synthetic lethality in TNBC by inhibiting homologous recombination, leading to cell cycle arrest and DNA damage. Optimizing the BRD4-PARP1 inhibitor provides a potential candidate drug for the treatment of TNBC in the future.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Medicine, Research & Experimental
Joni Jarvenpaa, Minna Rahnasto-Rilla, Maija Lahtela-Kakkonen, Jenni Kublbeck
Summary: Epigenetic regulators play a vital role in the development of cancer, and targeting these regulators may provide potential avenues for cancer treatment. The study shows that BET inhibitors have distinct effects on SIRTs and their target gene expression in various cancer cell lines, suggesting the potential for combination therapies in different cancers.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Oncology
Xiao-Feng Xie, Nan-Qiang Wu, Jin-Feng Wu, Guang-Lin Zhang, Jin-Feng Guo, Xue-Lian Chen, Cai-Wen Du
Summary: The combination of PARP inhibitor and CXCR4 inhibitor shows enhanced anti-tumor effect in BRCA-proficient triple-negative breast cancer, potentially broadening the indication of PARP inhibitors for this patient population.
Review
Biochemistry & Molecular Biology
Abhishek Wahi, Namish Manchanda, Priti Jain, Hemant R. Jadhav
Summary: Bromodomain and extraterminal (BET) proteins play a regulatory role in gene transcription by binding to acetylated lysine residues. BET inhibitors interfere with this binding and suppress transcription of cancer-related genes. Various strategies and inhibitors have been developed for cancer research and treatment, but their clinical effectiveness is limited, leading to the need for further development to improve efficacy and reduce side effects.
BIOORGANIC CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Yun-Song Yang, Xi Jin, Qin Li, Yi-Yu Chen, Fenfang Chen, Hena Zhang, Ying Su, Yi Xiao, Gen-Hong Di, Yi-Zhou Jiang, Shenglin Huang, Zhi-Ming Shao
Summary: This study explored the transcription variation landscape in triple-negative breast cancers (TNBCs) and identified a crucial oncogenic transcript MARCO-TST, which is associated with tumor progression and poor prognosis in TNBC patients. MARCO-TST enhances the stability of HIF-1 alpha by interacting with PLOD2, leading to metabolic dysregulation and the formation of a hypoxic tumor microenvironment in TNBC.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Krishan Kumar, Deepak Kanojia, David J. Bentrem, Rosa F. Hwang, Jonathan P. Butchar, Susheela Tridandapani, Hidayatullah G. Munshi
Summary: The study investigates the regulation of HYALs in pancreatic ductal adenocarcinoma (PDAC). It identifies the pro-tumorigenic role of HYAL1 and the involvement of BRD2 in its regulation. These findings enhance our understanding of the role and regulation of HYAL1 and provide a rationale for targeting HYAL1 in PDAC.
Review
Pharmacology & Pharmacy
Steven P. Angus, Jon S. Zawistowski, Gary L. Johnson
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 58
(2018)
Article
Biochemistry & Molecular Biology
Mahmud Hussain, Steven P. Angus, Brian Kuhlman
Article
Oncology
Steven P. Angus, Janet L. Oblinger, Timothy J. Stuhlmiller, Patrick A. DeSouza, Roberta L. Beauchamp, Luke Witt, Xin Chen, Justin T. Jordan, Thomas S. K. Gilbert, Anat Stemmer-Rachamimov, James F. Gusella, Scott R. Plotkin, Stephen J. Haggarty, Long-Sheng Chang, Gary L. Johnson, Vijaya Ramesh
Article
Multidisciplinary Sciences
Robert Allaway, Steve P. Angus, Roberta L. Beauchamp, Jaishri O. Blakeley, Marga Bott, Sarah S. Burns, Annemarie Carlstedt, Long-Sheng Chang, Xin Chen, D. Wade Clapp, Patrick A. Desouza, Serkan Erdin, Cristina Fernandez-Valle, Justin Guinney, James F. Gusella, Stephen J. Haggerty, Gary L. Johnson, Salvatore La Rosa, Helen Morrison, Alejandra M. Petrilli, Scott R. Plotkin, Abhishek Pratap, Vijaya Ramesh, Noah Sciaky, Anat Stemmer-Rachamimov, Tim J. Stuhlmiller, Michael E. Talkowski, D. Bradley Welling, Charles W. Yates, Jon S. Zawistowski, Wen-Ning Zhao
Article
Biochemistry & Molecular Biology
Jeffrey R. Gehlhausen, Eric Hawley, Benjamin Mark Wahle, Yongzheng He, Donna Edwards, Steven D. Rhodes, Jacquelyn D. Lajiness, Karl Staser, Shi Chen, Xianlin Yang, Jin Yuan, Xiaohong Li, Li Jiang, Abbi Smith, Waylan Bessler, George Sandusky, Anat Stemmer-Rachamimov, Timothy J. Stuhlmiller, Steven P. Angus, Gary L. Johnson, Grzegorz Nalepa, Charles W. Yates, D. Wade Clapp, Su-Jung Park
HUMAN MOLECULAR GENETICS
(2019)
Article
Oncology
Steven I. Park, Carolina P. Lin, Natalie Ren, Steven P. Angus, Dirk P. Dittmer, Michael Foote, Trevor Parton, Aadra P. Bhatt, Yuri D. Fedoriw, Daniel P. Roth, Marissa L. Cann, Gary L. Johnson, Blossom Damania
Article
Multidisciplinary Sciences
Andrew E. Hale, Donna Collins-McMillen, Erik M. Lenarcic, Suzu Igarashi, Jeremy P. Kamil, Felicia Goodrum, Nathaniel J. Moorman
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Oncology
Daniela Pucciarelli, Steven P. Angus, Benjamin Huang, Chi Zhang, Hiroki J. Nakaoka, Ganesh Krishnamurthi, Sourav Bandyopadhyay, D. Wade Clapp, Kevin Shannon, Gary L. Johnson, Jean L. Nakamura
MOLECULAR CANCER THERAPEUTICS
(2020)
Article
Oncology
Gaurav A. Mehta, Steven P. Angus, Christen A. Khella, Kevin Tong, Pooja Khanna, Shelley A. H. Dixon, Michael P. Verzi, Gary L. Johnson, Michael L. Gatza
Summary: The study reveals that the transcription factor SOX4 plays a key role in regulating PI3K signaling in basal-like breast cancer. SOX4 forms a complex with the SWI/SNF ATPase SMARCA4 to maintain an open chromatin conformation at the regulatory regions of TGFBR2, which in turn regulates TGFBR2 expression and PI3K signaling. This cooperative regulation of PI3K/Akt signaling by SOX4 and SMARCA4 may be essential in the genesis and progression of TNBC.
Article
Oncology
Steven P. Angus, Timothy J. Stuhlmiller, Gaurav Mehta, Samantha M. Bevill, Daniel R. Goulet, J. Felix Olivares-Quintero, Michael P. East, Maki Tanioka, Jon S. Zawistowski, Darshan Singh, Noah Sciaky, Xin Chen, Xiaping He, Naim U. Rashid, Lynn Chollet-Hinton, Cheng Fan, Matthew G. Soloway, Patricia A. Spears, Stuart Jefferys, Joel S. Parker, Kristalyn K. Gallagher, Andres Forero-Torres, Ian E. Krop, Alastair M. Thompson, Rashmi Murthy, Michael L. Gatza, Charles M. Perou, H. Shelton Earp, Lisa A. Carey, Gary L. Johnson
Summary: Inhibition of the pioneer transcription factor FOXA1 may disrupt adaptive responses of HER2+ breast cancer cells to drugs and enhance the efficacy of anti-HER2 therapy. Research has shown that HER2+ cells with higher responsiveness exhibit transcriptional and epigenetic changes related to FOXA1 when inhibited by lapatinib.
Article
Multidisciplinary Sciences
Long-Sheng Chang, Janet L. Oblinger, Abbi E. Smith, Marc Ferrer, Steven P. Angus, Eric Hawley, Alejandra M. Petrilli, Roberta L. Beauchamp, Lars Bjorn Riecken, Serkan Erdin, Ming Poi, Jie Huang, Waylan K. Bessler, Xiaohu Zhang, Rajarshi Guha, Craig Thomas, Sarah S. Burns, Thomas S. K. Gilbert, Li Jiang, Xiaohong Li, Qingbo Lu, Jin Yuan, Yongzheng He, Shelley A. H. Dixon, Andrea Masters, David R. Jones, Charles W. Yates, Stephen J. Haggarty, Salvatore La Rosa, D. Bradley Welling, Anat O. Stemmer-Rachamimov, Scott R. Plotkin, James F. Gusella, Justin Guinney, Helen Morrison, Vijaya Ramesh, Cristina Fernandez-Valle, Gary L. Johnson, Jaishri O. Blakeley, D. Wade Clapp
Summary: NF2 is a genetic syndrome caused by NF2 gene mutations, lacking FDA approved therapies, but brigatinib has shown potential efficacy for NF2 related tumors, acting through inhibition of multiple tyrosine kinases with a mechanism different from traditional drugs.
Article
Oncology
Alyssa C. Flint, Dana K. Mitchell, Steven P. Angus, Abbi E. Smith, Waylan Bessler, Li Jiang, Henry Mang, Xiaohong Li, Qingbo Lu, Brooke Rodriguez, George E. Sandusky, Andi R. Masters, Chi Zhang, Pengtao Dang, Jenna Koenig, Gary L. Johnson, Weihua Shen, Jiangang Liu, Amit Aggarwal, Gregory P. Donoho, Melinda D. Willard, Shripad Bhagwat, D. Wade Clapp, Steven D. Rhodes
Summary: By utilizing an integrated multi-omic approach, we identified novel therapeutic targets for the treatment of peripheral nerve sheath tumors, particularly plexiform neurofibromas (PNF), in individuals with neurofibromatosis type 1 (NF1). Through experimental studies on a mouse model, we discovered that inhibiting the CDK4/6 and RAS/MAPK pathways showed significant efficacy in reducing PNF tumor burden. These findings provide a promising rationale for clinical translation and treatment of PNF and other related tumors.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Hailey E. Brighton, Steven P. Angus, Tao Bo, Jose Roques, Alicia C. Tagliatela, David B. Darr, Kubra Karagoz, Noah Sciaky, Michael L. Gatza, Norman E. Sharpless, Gary L. Johnson, James E. Bear