9EFC

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with TO-588

This is a non-PDB format compatible entry.

Summary for 9EFC

• Entry DOI: 10.2210/pdb9efc/pdb
• Descriptor: Hdac6 protein, N-hydroxy-4-({(methanesulfonyl)[(pyridin-3-yl)methyl]amino}methyl)benzamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: potassium ion binding, alkali metal ion binding, ion binding, cation binding, metal ion binding, catalytic activity, hydrolase activity, deacetylase activity, protein deacetylase activity, acting on a protein, acting on carbon-nitrogen (but not peptide) bonds, in linear amides, tubulin deacetylase activity, zinc ion binding, transition metal ion binding, metal binding protein
• Biological source: Danio rerio (zebrafish)
• Total number of polymer chains: 2
• Total formula weight: 80582.07

Authors

Erdogan, F.,Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2024-11-20, release date: 2024-12-04, Last modification date: 2025-09-24)

Primary citation

Olaoye, O.O.,Erdogan, F.,Gracia-Hernandez, M.,Garcha, H.K.,Sedighi, A.,Ashraf, Q.F.,Nawar, N.,Geletu, M.,Seo, H.S.,Abdallah, D.I.,Abdeldayem, A.,Hassan, M.M.,Dhe-Paganon, S.,de Araujo, E.D.,Villagra, A.,Gunning, P.T.
Improved Pharmacokinetic Profiles of HDAC6 Inhibitors via Cap Group Modifications.
J.Med.Chem., 68:18216-18229, 2025

PubMed Abstract: Hydroxamic acid (HA)-based HDAC inhibitors often suffer from poor pharmacokinetic (PK) profiles, limiting their in vivo applications. Cap group modification offers a promising strategy to address these challenges. Here, we optimized the cap group of TO-317, a selective HDAC6 inhibitor with a bisected cap structure, generating 26 analogs with comparable or improved HDAC6 binding affinity and selectivity. Replacing the redundant tetrafluorobenzene sulfonamide cap while retaining the essential picolyl cap group preserved the critical H614 hydrogen bond, as confirmed by X-ray crystallography (1.24-1.27 Å resolution) of five analogs. Analog , featuring a 2-chlorobenzene sulfonamide cap, demonstrated a 120-fold enhancement in plasma concentration in mice compared to that of TO-317. Preclinical studies showed that analog achieved 56% tumor growth inhibition in an SM1 melanoma murine model without observed toxicity. These findings highlight cap group optimization as a powerful approach to enhance HA-based HDAC inhibitors for advanced preclinical and clinical development.

PubMed: 40864867
DOI: 10.1021/acs.jmedchem.5c00479

Experimental method

X-RAY DIFFRACTION (1.26 Å)