Structure-Based
Discovery and Optimization of Furo[3,2‑c]pyridin-4(5H)‑one Derivatives
as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal
Domain (BET) Inhibitors
Posted on 2022-03-25 - 19:16
Pan-bromodomain and extra terminal
(Pan-BET) inhibitors show profound
efficacy but exhibit pharmacology-driven toxicities in clinical trials.
The development of domain-selective BET inhibitors to separate efficacy
and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel
BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory
concentration (IC50) value of 0.79 nM and displayed 354-fold
selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold
BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple
tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while
showing weak cytotoxicity against the normal lung fibroblast cell
line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These
data indicate that 8l may serve as a new and valuable
lead compound for the development of potential therapeutics against
acute myeloid leukemia (AML).
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Li, Junhua; Zhang, Cheng; Xu, Hongrui; Wang, Chao; Dong, Ruibo; Shen, Hui; et al. (2022). Structure-Based
Discovery and Optimization of Furo[3,2‑c]pyridin-4(5H)‑one Derivatives
as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal
Domain (BET) Inhibitors. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.2c00100