8GD4

Crystal Structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with DMFO Inhibitor 6

Summary for 8GD4

• Entry DOI: 10.2210/pdb8gd4/pdb
• Descriptor: Hdac6 protein, 2-(benzylamino)-N'-(difluoroacetyl)pyrimidine-5-carbohydrazide, ZINC ION, ... (5 entities in total)
• Functional Keywords: hydrolase, histone deacetylase, inhibitor, metallohydrolase
• Biological source: Danio rerio (zebrafish)
• Total number of polymer chains: 2
• Total formula weight: 81500.74

Authors

Watson, P.R.,Craigin, A.D.,Christianson, D.W. (deposition date: 2023-03-03, release date: 2023-10-04, Last modification date: 2023-10-25)

Primary citation

Konig, B.,Watson, P.R.,Ressing, N.,Cragin, A.D.,Schaker-Hubner, L.,Christianson, D.W.,Hansen, F.K.
Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6 .
J.Med.Chem., 66:13821-13837, 2023

PubMed Abstract: Histone deacetylase (HDAC6) is an important drug target in oncological and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize hydroxamic acids as a zinc-binding group, which limits therapeutic opportunities due to its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of by the zinc-bound water at the sp carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields deprotonated difluoroacetylhydrazide as active species. The strong anionic zinc coordination of and the binding of the difluoromethyl moiety in the P571 pocket finally result in an essentially irreversible inhibition of HDAC6.

PubMed: 37782298
DOI: 10.1021/acs.jmedchem.3c01345

Experimental method

X-RAY DIFFRACTION (2 Å)