HDAC10型
HDAC6型
化学
组蛋白脱乙酰基酶
基因敲除
生物化学
药理学
组蛋白
计算生物学
癌症研究
医学
生物
基因
作者
Magalie Géraldy,Michael Morgen,Peter Sehr,Raphael R. Steimbach,Davide Moi,Johannes Ridinger,Ina Oehme,Olaf Witt,Mona Malz,Mauro S. Nogueira,Oliver Koch,Nikolas Gunkel,Aubry K. Miller
标识
DOI:10.1021/acs.jmedchem.8b01936
摘要
The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.
科研通智能强力驱动
Strongly Powered by AbleSci AI