Ram K. Modukuri; Zhifeng Yu; Zhi Tan; Hai Minh Ta; Melek Nihan Ucisik; Zhuang Jin; Justin L. Anglin; Kiran L. Sharma; Pranavanand Nyshadham; Feng Li; Kevin Riehle; John C. Faver; Kevin Duong; Sureshbabu Nagarajan; Nicholas Simmons; Stephen S. Palmer; Mingxing Teng; Damian W. Young; Joanna S. Yi; Choel Kim; Martin M. Matzuk
Proc. Natl. Acad. Sci. USA, 2022, 119(22), e2122506119
https://doi.org/10.1073/pnas.2122506119

Abstract

SignificanceBET bromodomain inhibition is therapeutic in multiple diseases; however, pan-BET inhibitors have induced significant myelosuppression and gastrointestinal toxicity, perhaps due to inhibition of both tandem bromodomains (BD) of all BET family members. However, selective inhibition of just the first BD (BD1) phenocopies pan-BET inhibitor activity in preclinical models of cancer, other diseases, and, for BRDT, in the testes for a contraceptive effect. Here, we leveraged our multibillion-molecule collection of DNA-encoded chemical libraries (DECLs) to identify BET BD1-selective inhibitors of specific chirality with high potency, stability, and good cellular activity. Our findings highlight the robustness and efficiency of the DECL platform to identify specific, potent protein binders that have promise as potential anticancer and anti-inflammatory agents and as male contraceptives.