Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction.

Autor:	Beshore DC; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Adam GC; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Barnard RJO; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Burlein C; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Gallicchio SN; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Holloway MK; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Krosky D; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Lemaire W; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Myers RW; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Patel S; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Plotkin MA; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Powell DA; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Rada V; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Cox CD; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Coleman PJ; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Klein DJ; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Wolkenberg SE; MRL, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Mar 07; Vol. 12 (4), pp. 540-547. Date of Electronic Publication: 2021 Mar 07 (Print Publication: 2021).
DOI:	10.1021/acsmedchemlett.1c00074
Abstrakt:	A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors. Competing Interests: The authors declare the following competing financial interest(s): Authors are current or former employees of Merck & Co., Inc., Kenilworth, NJ, USA and potentially own stock and/or hold stock options in the Company. (© 2021 American Chemical Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu