Journal ArticleDOI
Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation
Xiaoqian Xue,Yan Zhang,Liu Zhaoxuan,Liu Zhaoxuan,Ming Song,Yanli Xing,Yanli Xing,Qiuping Xiang,Qiuping Xiang,Zhen Wang,Zhengchao Tu,Y. Zhou,Ke Ding,Yong Xu +13 more
TLDR
The identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS).Abstract:
The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective ...read more
Citations
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Journal ArticleDOI
Drug Discovery Targeting Bromodomain-Containing Protein 4.
TL;DR: The advances in drug discovery and development of BRD4 inhibitors are summarized by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential.
Journal ArticleDOI
Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression
Chong Qin,Yang Hu,Bing Zhou,Ester Fernandez-Salas,Chao Yie Yang,Liu Liu,Donna McEachern,Sally Przybranowski,Mi Wang,Jeanne A. Stuckey,Jennifer L. Meagher,Longchuan Bai,Zhuo Chen,Mei Lin,Jiuling Yang,Danya N. Ziazadeh,Fuming Xu,Jiantao Hu,Weiguo Xiang,Liyue Huang,Siwei Li,Bo Wen,Duxin Sun,Shaomeng Wang +23 more
TL;DR: A structure-guided design of [1,4]oxazepines as a new class of BET inhibitors is described and the subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders are described.
Journal ArticleDOI
Targeting Brd4 for cancer therapy: inhibitors and degraders.
TL;DR: Recently, selective degradation of target proteins by small bifunctional molecules (PROTACs) has emerged as an attractive drug discovery approach owing to the advantages it could offer over traditional small-molecule inhibitors.
Journal ArticleDOI
Cobalt-Catalyzed Direct Carbonylative Synthesis of Free (NH)-Benzo[cd]indol-2(1H)-ones from Naphthylamides.
TL;DR: A cobalt-catalyzed C-H carbonylation of naphthylamides for the synthesis of benzo[ cd]indol-2(1 H)-one scaffolds has been developed and the total synthesis of BET bromodomain inhibitors A and B was accomplished.
Journal ArticleDOI
The compromise of virtual screening and its impact on drug discovery
Olivia Slater,Maria Kontoyianni +1 more
TL;DR: Integration of approaches, subjective hit selection guided by knowledge of the receptor or endogenous ligand, libraries driven by experimental guides, validation studies to identify the best docking/scoring that reproduces experimental findings, constraints regarding receptor–ligand interactions, thoroughly designed methodologies, and predefined cutoff scoring criteria strengthen VS’s position in pharmaceutical research.
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