组蛋白N末端赖氨酸的乙酰化在转录调控中有重要作用。多种含Bromodomain的蛋白可以与乙酰化赖氨酸结合并招募其它染色质因子来协同调控基因转录,这一过程与人体很多疾病的产生和发展密切相关。本文中对近年来Bromodomain-containing pro...组蛋白N末端赖氨酸的乙酰化在转录调控中有重要作用。多种含Bromodomain的蛋白可以与乙酰化赖氨酸结合并招募其它染色质因子来协同调控基因转录,这一过程与人体很多疾病的产生和发展密切相关。本文中对近年来Bromodomain-containing protein 9(BRD9)选择性的小分子抑制剂的研究进展进行了总结。展开更多
The bromodomain-containing protein 9(BRD9)is a core subunit of mammalian SWI/SNF chromatin remodeling complex termed ncBAF.BRD9 has emerged as a potential target for anticancer drugs,particularly in the treatment of a...The bromodomain-containing protein 9(BRD9)is a core subunit of mammalian SWI/SNF chromatin remodeling complex termed ncBAF.BRD9 has emerged as a potential target for anticancer drugs,particularly in the treatment of acute myeloid leukemia(AML).Herein,we reported 10m(Y22073)and 10t as new BRD9 selective bromodomain inhibitors.Crystallographic studies revealed that the key active imidazolyl group discovered from structure-activity relationship(SAR)can induce Phe163 flipping and significantly enhance the cellular potency of the compounds,making 10m the first BRD9 selective inhibitor with significant cellular activity against AML cells.We also validated the critical role of imidazolyl groups by modifying existing BRD9 inhibitors.The representative compounds 10m and 10t demonstrated potent binding affinity,outstanding selectivity toward BRD9 bromodomain,and significantly inhibited the proliferation of AML cell lines.10m also showed good metabolic stability,solubility and pharmacokinetic properties.Additionally,oral administration of compounds 10m and 10t exhibited potent anti-tumor efficacy in the MV4-11 xenograft mouse model.The potent,selective,and orally available BRD9 bromodomain inhibitors may address the challenges of weak cellular activity and limited phenotypic efficacy faced by BRD9 inhibitors,and serve as new lead compounds for the development of anticancer agents for the treatment of AML.展开更多
Bromodomain-containing protein 9(BRD9)is a core subunit of chromatin remodeling SWI/SNF ncBAF complex.This complex,particularly the BRD9 subunit,is frequently subject to recurrent somatic mutations in various human ca...Bromodomain-containing protein 9(BRD9)is a core subunit of chromatin remodeling SWI/SNF ncBAF complex.This complex,particularly the BRD9 subunit,is frequently subject to recurrent somatic mutations in various human cancers1,2.BRD9 functions as a chromatin reader of histones,specifically recognizing and binding to acetylated or butyrylated histones through its conserved bromodomain,thereby regulating chromatin states3,4.展开更多
文摘组蛋白N末端赖氨酸的乙酰化在转录调控中有重要作用。多种含Bromodomain的蛋白可以与乙酰化赖氨酸结合并招募其它染色质因子来协同调控基因转录,这一过程与人体很多疾病的产生和发展密切相关。本文中对近年来Bromodomain-containing protein 9(BRD9)选择性的小分子抑制剂的研究进展进行了总结。
基金supported in part by grants from the National Key R&D Program of China(Nos.2022YFE0210600 and 2019YFE0123700)the National Natural Science Foundation of China(Nos.22307116 and 82173745)+4 种基金the Guangdong Basic and Applied Basic Research Foundation(No.2024A1515012186,China)the Science and Technology Program of Guangzhou(No.2025A04J4520,China)Guangdong Province Grant for Belt and Road Joint Laboratory(No.2022B1212050004,China)the Youth Innovation Promotion Association CAS(No.2023372,China)the Basic Research Project of Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences(Nos.GIBHBRP24-03 and GIBHBRP24-04,China).
文摘The bromodomain-containing protein 9(BRD9)is a core subunit of mammalian SWI/SNF chromatin remodeling complex termed ncBAF.BRD9 has emerged as a potential target for anticancer drugs,particularly in the treatment of acute myeloid leukemia(AML).Herein,we reported 10m(Y22073)and 10t as new BRD9 selective bromodomain inhibitors.Crystallographic studies revealed that the key active imidazolyl group discovered from structure-activity relationship(SAR)can induce Phe163 flipping and significantly enhance the cellular potency of the compounds,making 10m the first BRD9 selective inhibitor with significant cellular activity against AML cells.We also validated the critical role of imidazolyl groups by modifying existing BRD9 inhibitors.The representative compounds 10m and 10t demonstrated potent binding affinity,outstanding selectivity toward BRD9 bromodomain,and significantly inhibited the proliferation of AML cell lines.10m also showed good metabolic stability,solubility and pharmacokinetic properties.Additionally,oral administration of compounds 10m and 10t exhibited potent anti-tumor efficacy in the MV4-11 xenograft mouse model.The potent,selective,and orally available BRD9 bromodomain inhibitors may address the challenges of weak cellular activity and limited phenotypic efficacy faced by BRD9 inhibitors,and serve as new lead compounds for the development of anticancer agents for the treatment of AML.
文摘Bromodomain-containing protein 9(BRD9)is a core subunit of chromatin remodeling SWI/SNF ncBAF complex.This complex,particularly the BRD9 subunit,is frequently subject to recurrent somatic mutations in various human cancers1,2.BRD9 functions as a chromatin reader of histones,specifically recognizing and binding to acetylated or butyrylated histones through its conserved bromodomain,thereby regulating chromatin states3,4.
