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Lysine-targeting, covalent inhibitors of bromodomain BD1 of BET proteins in live cells and animals

ABSTRACT: We report herein a set of activity-based probes (ABPs; P3-P7) based on various lysine-reactive covalent warheads capable of global profiling of ligandable lysine within BRDs in live cells and animals. Chemoproteomic experiments with P7 by utilizing 2-ethynylbenzaldehyde (EBA) identified 18 endogenous BRDs, thus giving a global landscape of ligandable lysines in BRDs.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Yusheng Xie

PROVIDER: PXD058513 | iProX | Thu Apr 10 00:00:00 BST 2025

REPOSITORIES: iProX

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Lysine-Targeting, Covalent Inhibitors of Bromodomain BD1 of BET Proteins in Live Cells and Animals.

Li Tao T Zhang Wenjie W Wang Yiqing Y Xu Guangyu G Miao Fengfei F Chen Peng P Tang Guanghui G Ze Xiaotong X Xiang Jing J Yan Jiaqian J Wang Miaomiao M Liu Min M Wang Xiaojie X Tang Wei W Yi Fan F Zhang Zhi-Min ZM Wang Rui R Yao Shao Q SQ Xie Yusheng Y

Angewandte Chemie (International ed. in English) 20250510 28

The bromodomain extra-terminal (BET) family of proteins are valuable therapeutic targets for cancer and other diseases. The adverse events of current pan-BET inhibitors (BETi) make the development of BET BD1- or BD2-selective inhibitors as a fresh avenue to overcome safety challenges. On the basis of various lysine-reactive covalent warheads herein we report a set of activity-based probes (ABPs; P3-P7) capable of global profiling of ligandable lysines within bromodomains (BRDs) in live cells and ...[more]

PMID: 40313007

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Lysine-targeting, covalent inhibitors of bromodomain BD1 of BET proteins in live cells and animals

Project description:Bromodomain (BRD) is an epigenetic reader of acetylated lysine. It has emerged as a therapeutic target for cancer and other diseases. Current nonselective BRD inhibitors (BRDis) face several adverse events (i.e. gastrointestinal toxicity and thrombocytopenia), making the development of target covalent inhibitor (TCI) for BD1/2 as a fresh avenue to overcome safety challenges. We report herein a set of activity-based probes (ABPs; P3-P7) based on various lysine-reactive covalent warheads capable of global profiling of ligandable lysine within BRDs in live cells and animals. Chemoproteomic experiments with P7 by utilizing 2-ethynylbenzaldehyde (EBA) identified 16 endogenous BRDs, thus giving a global landscape of ligandable lysines in BRDs. By further introducing EBA and salicylaldehyde into PLX51107 (a non-covalent BRDi), we generated novel irreversible (BDS1-4) and reversible (BDS5-6) lysine-reactive TCIs. Mass spectrometry and X-ray crystallography confirmed the successful covalent engagement between the covalent warhead and lysine near Kac binding site. BDS4 showed 104-fold selectivity for BD1 over BD2 with prolonged anti-cancer effect than non-covalent BRDi. Importantly, BDS4 retained robust activity against fibrosis in cells and animals in comparison to the marginal effect of BD2 inhibitor RVX-208. Our work serves as a useful tool to delineate the distinct function of BD1 and BD2.

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A Proteome-Wide Atlas of Lysine-Reactive Chemistry

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Lysine-targeting, covalent inhibitors of bromodomain BD1 of BET proteins in live cells and animals

Project description:Lysine-targeting, covalent inhibitors of bromodomain BD1 of BET proteins in live cells and animals

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O-Cyanobenzaldehydes (CNBA) Irreversibly Modify both Bur-ied and Exposed Lysine Residues in Live Cells

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2023-05-18 | PXD042307 | Pride

Development of potent and selective KDM5 covalent inhibitors

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