1. Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit
Simon Taylor, Cassie Messenger, Inmaculada Rioja, Ian D Wall, Emmanuel H Demont, James R J Gray, Alex Phillipou, Stephen J Atkinson, Gang Yao, Patricia Medeiros, Alex Preston, Laura J Kaushansky, Paola Grandi, Alexander L Satz, Robert J Watson, Rab K Prinjha, Chun-Wa Chung, Francesco Rianjongdee J Med Chem . 2021 Aug 12;64(15):10806-10833. doi: 10.1021/acs.jmedchem.1c00412.
Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified60(GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.
2. Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer
Chang H Park, Vasudha Sehgal, Steve Fidanze, Mai H Bui, Daniel H Albert, Stacey L Fossey, George S Sheppard, Maricel Torrent, Gaurav Mehta, Lu Zhang, Xiaoyu Lin, Le Wang, Paul Hessler, Warren M Kati, Xiaoli Huang, Lisa A Hasvold, John J Nicolette, Sanjay C Panchal, Richard J Bellin, Keith F McDaniel, Kenton Longenecker, Srinivasa R Mantena, Denise Wilcox, Tamar Uziel, Lloyd T Lam, Lance Bigelow, Yu Shen, Dachun Liu, Xin Lu, John K Pratt, Chaohong Sun, Joshua P Plotnik, Saul H Rosenberg, Emily J Faivre Nature . 2020 Feb;578(7794):306-310. doi: 10.1038/s41586-020-1930-8.
Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
3. BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2
Rémy Robinot, Marco Vignuzzi, Martin Kampmann, James Nunez, Lucia Carrau, Jennifer Oki, Shion A Lim, Avi J Samelson, Lisa A Chakrabarti, Jared Carlson-Stevermer, Alice Mac Kain, Bruce R Conklin, Merissa Chen, Benjamin R TenOever, Veronica V Rezelj, Gokul N Ramadoss, Sarah J Rockwood, Jonathan S Weissman, Kevin Holden, James A Wells, Jianhui Wang, Quang Dinh Tran, Xiaoyan Guo, Ruilin Tian, Travis Maures, Na Liu, Irene Lui bioRxiv . 2021 Sep 20;2021.01.19.427194. doi: 10.1101/2021.01.19.427194.
SARS-CoV-2 infection of human cells is initiated by the binding of the viral Spike protein to its cell-surface receptor ACE2. We conducted a targeted CRISPRi screen to uncover druggable pathways controlling Spike protein binding to human cells. We found that the protein BRD2 is required forACE2transcription in human lung epithelial cells and cardiomyocytes, and BRD2 inhibitors currently evaluated in clinical trials potently block endogenousACE2expression and SARS-CoV-2 infection of human cells, including those of human nasal epithelia. Moreover, pharmacological BRD2 inhibition with the drug ABBV-744 inhibited SARS-CoV-2 replication in Syrian hamsters. We also found that BRD2 controls transcription of several other genes induced upon SARS-CoV-2 infection, including the interferon response, which in turn regulates the antiviral response. Together, our results pinpoint BRD2 as a potent and essential regulator of the host response to SARS-CoV-2 infection and highlight the potential of BRD2 as a novel therapeutic target for COVID-19.
