Lysine-Targeting, Covalent Inhibitors of Bromodomain BD1 of BET Proteins in Live Cells and Animals
Tao Li
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
These authors contributed equally to this work.
Search for more papers by this authorWenjie Zhang
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
These authors contributed equally to this work.
Search for more papers by this authorYiqing Wang
State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 511436 China
These authors contributed equally to this work.
Search for more papers by this authorGuangyu Xu
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
These authors contributed equally to this work.
Search for more papers by this authorFengfei Miao
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore, 117544 Singapore
Search for more papers by this authorPeng Chen
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore, 117544 Singapore
Search for more papers by this authorGuanghui Tang
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore, 117544 Singapore
Search for more papers by this authorXiaotong Ze
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorJing Xiang
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorJiaqian Yan
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorDr. Miaomiao Wang
Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong, 250033 China
Search for more papers by this authorMin Liu
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorXiaojie Wang
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorWei Tang
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorProf. Dr. Fan Yi
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorCorresponding Author
Prof. Dr. Zhi-Min Zhang
State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 511436 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Dr. Rui Wang
Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, 518118 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Prof. Dr. Shao Q Yao
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore, 117544 Singapore
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Prof. Dr. Yusheng Xie
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorTao Li
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
These authors contributed equally to this work.
Search for more papers by this authorWenjie Zhang
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
These authors contributed equally to this work.
Search for more papers by this authorYiqing Wang
State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 511436 China
These authors contributed equally to this work.
Search for more papers by this authorGuangyu Xu
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
These authors contributed equally to this work.
Search for more papers by this authorFengfei Miao
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore, 117544 Singapore
Search for more papers by this authorPeng Chen
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore, 117544 Singapore
Search for more papers by this authorGuanghui Tang
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore, 117544 Singapore
Search for more papers by this authorXiaotong Ze
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorJing Xiang
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorJiaqian Yan
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorDr. Miaomiao Wang
Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong, 250033 China
Search for more papers by this authorMin Liu
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorXiaojie Wang
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorWei Tang
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorProf. Dr. Fan Yi
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
Search for more papers by this authorCorresponding Author
Prof. Dr. Zhi-Min Zhang
State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 511436 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Dr. Rui Wang
Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, 518118 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Prof. Dr. Shao Q Yao
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore, 117544 Singapore
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Prof. Dr. Yusheng Xie
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorGraphical Abstract
We successfully developed the first BD1-targted covalent inhibitor (TCI), BDS4, by utilizing 2-ethynylbenzaldehyde (EBA). Importantly, BDS4 retained robust activity against fibrosis in cells and animals when compared to the marginal effects of BD2 inhibitor RVX-208. Our developed tool showed clear advantages of long-lasting domain-selective TCI in delineating the district function of BD1 and BD2.
Abstract
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 animals. Chemoproteomic experiments with P7, which utilizes 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 noncovalent BETi), we generated lysine-reactive, irreversible (BDS1–4) and reversible (BDS5–6) BD1 covalent inhibitors. Mass spectrometry and X-ray crystallography confirmed the successful covalent engagement between EBA and K91 near the acetylated lysine (Kac)-binding site of BD1 in BRD4. BDS4 showed 104-fold selectivity for BD1 over BD2 with prolonged anticancer effects. Importantly, BDS4 retained robust activity against fibrosis in cells and animals when compared to RVX-208 (a reported BD2-selective noncovalent inhibitor), which showed only marginal effects. Our work serves as a useful tool to delineate distinct functions of BD1 and BD2 in future studies.
Conflict of Interests
Y.X., S.Y., M.W., T.L., W.Z., X.Z., and J.Y. are inventors on provisional patents (China Provisional Patent Application no.: 2024117297803, 2024117641745) related to this work.
Open Research
Data Availability Statement
The data that support the findings of this study are available in the Supporting Information of this article.
Supporting Information
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