Christianson David W, Stollmaier Juana Goulart, Czarnecki Briana Abigail R
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, 19104-6323, United States.
bioRxiv. 2025 Jan 4:2025.01.04.631333. doi: 10.1101/2025.01.04.631333.
Organoselenocyanates have attracted considerable attention in recent years due to their therapeutic potential and versatility in medicinal chemistry. Here, we report on the mechanism of inhibition by 5-phenylcarbamoylpentyl selenocyanide (SelSA-2), an analogue of the well-characterized histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, a.k.a. Vorinostat). We show that histone deacetylases 6 and 10 can promote selenocyanate hydrolysis to generate a selenolate anion, and we explore the redox chemistry of selenium as it modulates inhibitory activity through reversible formation of the diselenide. The 2.15 Å-resolution crystal structure of histone deacetylase 6 cocrystallized with SelSA-2 conclusively demonstrates that it is not the selenocyanate, but instead the selenolate anion, that is the active pharmacophore responsible for enzyme inhibition.
近年来，有机硒氰酸盐因其治疗潜力和在药物化学中的多功能性而备受关注。在此，我们报告5-苯基氨基甲酰基戊基硒氰化物（SelSA-2）的抑制机制，它是特征明确的组蛋白脱乙酰酶抑制剂辛二酰苯胺异羟肟酸（SAHA，又名伏立诺他）的类似物。我们表明，组蛋白脱乙酰酶6和10可促进硒氰酸盐水解生成硒醇盐阴离子，并且我们探索了硒的氧化还原化学，因为它通过二硒化物的可逆形成来调节抑制活性。与SelSA-2共结晶的组蛋白脱乙酰酶6的2.15 Å分辨率晶体结构最终证明，负责酶抑制的活性药效基团不是硒氰酸盐，而是硒醇盐阴离子。
