8CJ7

HDAC6 selective degraded (difluoromethyl)-1,3,4-oxadiazole substrate inhibitor

Summary for 8CJ7

• Entry DOI: 10.2210/pdb8cj7/pdb
• Descriptor: Histone deacetylase 6, POTASSIUM ION, ZINC ION, ... (6 entities in total)
• Functional Keywords: inhibitor, small molecule hydrazide, hdac6, oxadiazole, histone, hydrolase
• Biological source: Danio rerio (zebrafish)
• Total number of polymer chains: 3
• Total formula weight: 122641.26

Authors

Sandmark, J.,Ek, M.,Ripa, L. (deposition date: 2023-02-12, release date: 2023-10-18, Last modification date: 2023-11-01)

Primary citation

Ripa, L.,Sandmark, J.,Hughes, G.,Shamovsky, I.,Gunnarsson, A.,Johansson, J.,Llinas, A.,Collins, M.,Jung, B.,Noven, A.,Pemberton, N.,Mogemark, M.,Xiong, Y.,Li, Q.,Tangefjord, S.,Ek, M.,Astrand, A.
Selective and Bioavailable HDAC6 2-(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism.
J.Med.Chem., 66:14188-14207, 2023

PubMed Abstract: Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family mainly targeting cytosolic nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. We describe the identification and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles (DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing structure-activity relationships and performing quantum mechanical calculations of the HDAC6 catalytic mechanism, we show that potent oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism for the bioactivation. We also observe that the inherent electrophilicity of the oxadiazoles makes them prone to degradation in water solution and the generation of potentially toxic products cannot be ruled out, limiting the developability for chronic diseases. However, the oxadiazoles demonstrate high oral bioavailability and low in vivo clearance and are excellent tools for studying the role of HDAC6 in vitro and in vivo in rats and mice.

PubMed: 37797307
DOI: 10.1021/acs.jmedchem.3c01269

Experimental method

X-RAY DIFFRACTION (1.51 Å)