Journal
ACS CHEMICAL BIOLOGY
Volume 10, Issue 3, Pages 687-692Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb500767c
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Funding
- National Science Foundation of China [21203257, 21272289]
- National Institute of Health [R01-GM079223, R21-GM097530]
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Development of isoform-selective histone deacetylase (HDAC) inhibitors is of great biological and medical interest. Among 11 zinc-dependent HDAC isoforms, it is particularly challenging to achieve isoform inhibition selectivity between HDAC1 and HDAC2 due to their very high structural similarities. In this work, by developing and applying a novel de novo reaction-mechanism-based inhibitor design strategy to exploit the reactivity difference, we have discovered the first HDAC2-selective inhibitor, beta-hydroxymethyl chalcone. Our bioassay experiments show that this new compound has a unique time-dependent selective inhibition on HDAC2, leading to about 20-fold isoform-selectivity against HDAC1. Furthermore, our ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to study reactions in biological systems, have elucidated how the beta-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2.
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