Design, synthesis, and biological evaluation of BRD4 degraders.

Epigenetic mechanisms for controlling gene expression through heritable modifications to DNA, RNA, and proteins, are essential processes in maintaining cellular homeostasis. As a result of their central role in human diseases, the proteins responsible for adding, removing, or recognizing epigenetic modifications have emerged as viable drug targets. In the case of lysine‐ε‐N‐acetylation (Kac), bromodomains serve as recognition modules (“readers”) of this activating epigenetic mark and competition of the bromodomain‐Kac interaction with small‐molecule inhibitors is an attractive strategy to control aberrant bromodomain‐mediated gene expression. The bromodomain and extra‐terminal (BET) family proteins contain eight similar bromodomains. These BET bromodomains are among the more commonly studied bromodomain classes with numerous pan‐BET inhibitors showing promising anticancer and anti‐inflammatory efficacy. However, these results have yet to translate into Food and Drug Administration‐approved drugs, in part due to a high degree of on‐target toxicities associated with pan‐BET inhibition. Improved selectivity within the BET‐family has been proposed to alleviate these concerns. In this review, we analyze the reported BET‐domain selective inhibitors from a structural perspective. We highlight three essential characteristics of the reported molecules in generating domain selectivity, binding affinity, and mimicking Kac molecular recognition. In several cases, we provide insight into the design of molecules with improved specificity for individual BET‐bromodomains. This review provides a perspective on the current state of the field as this exciting class of inhibitors continue to be evaluated in the clinic.

Recent progress and structural analyses of domain‐selective BET inhibitors

Rational design, synthesis and biological evaluation of benzo[d]isoxazole derivatives as potent BET bivalent inhibitors for potential treatment of prostate cancer

Abstract Bromodomain (BD) is an evolutionarily conserved protein module found in 46 different BD-containing proteins (BCPs). BD acts as a specific reader for acetylated lysine residues (KAc) and serves an essential role in transcriptional regulation, chromatin remodeling, DNA damage repair, and cell proliferation. On the other hand, BCPs have been shown to be involved in the pathogenesis of a variety of diseases, including cancers, inflammation, cardiovascular diseases, and viral infections. Over the past decade, researchers have brought new therapeutic strategies to relevant diseases by inhibiting the activity or downregulating the expression of BCPs to interfere with the transcription of pathogenic genes. An increasing number of potent inhibitors and degraders of BCPs have been developed, some of which are already in clinical trials. In this paper, we provide a comprehensive review of recent advances in the study of drugs that inhibit or down-regulate BCPs, focusing on the development history, molecular structure, biological activity, interaction with BCPs and therapeutic potentials of these drugs. In addition, we discuss current challenges, issues to be addressed and future research directions for the development of BCPs inhibitors. Lessons learned from the successful or unsuccessful development experiences of these inhibitors or degraders will facilitate the further development of efficient, selective and less toxic inhibitors of BCPs and eventually achieve drug application in the clinic. 

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Targeting bromodomain-containing proteins: research advances of drug discovery

Multivalency is an attractive strategy for effective binding to target protein. Bromodomain and extra-terminal (BET) family features two tandem bromodomains (BD1, BD2), which are considered to be potential new targets for prostate cancer. Herein, we report the rational design, optimization, and evaluation of a class of novel BET bivalent inhibitors based on our monovalent BET inhibitor 7 (Y06037). The representative bivalent inhibitor 17b effectively inhibited the cell growth of LNCaP, exhibiting 32 folds more potency than monovalent inhibitor 7. Besides, 17b induced 95.1 % PSA regression in LNCaP cell at 2 μM. Docking study was further carried out to reveal the potential binding mode of 17b with two BET bromodomains. Our study demonstrates that 17b (Y13021) is a promising BET bivalent inhibitor for the treatment of prostate cancer.

Rational design, synthesis and biological evaluation of benzo[d]isoxazole derivatives as potent BET bivalent inhibitors for potential treatment of prostate cancer.

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).

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.

Ruibo Dong

Papers

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.