6FYZ

Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor

Summary for 6FYZ

• Entry DOI: 10.2210/pdb6fyz/pdb
• Descriptor: Histone deacetylase 4, (2~{S})-2-(2-fluorophenyl)-2-[4-(2-methylpyrimidin-5-yl)phenyl]-~{N}-oxidanyl-ethanamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: hydroxamic acid, cns-penetrant, hdac4 inhibition, class iia hdac inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 129866.38

Authors

Luckhurst, C.A.,Maillard, M.C.,Dominguez, C. (deposition date: 2018-03-13, release date: 2018-12-05, Last modification date: 2024-01-17)

Primary citation

Luckhurst, C.A.,Aziz, O.,Beaumont, V.,Burli, R.W.,Breccia, P.,Maillard, M.C.,Haughan, A.F.,Lamers, M.,Leonard, P.,Matthews, K.L.,Raphy, G.,Stott, A.J.,Munoz-Sanjuan, I.,Thomas, B.,Wall, M.,Wishart, G.,Yates, D.,Dominguez, C.
Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor.
Bioorg. Med. Chem. Lett., 29:83-88, 2019

PubMed Abstract: We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.

PubMed: 30463802
DOI: 10.1016/j.bmcl.2018.11.009

Experimental method

X-RAY DIFFRACTION (2.15 Å)