28OI
The crystal structure of zebrafish HDAC6 CD2 in complex with compound 2
This is a non-PDB format compatible entry.
Summary for 28OI
| Entry DOI | 10.2210/pdb28oi/pdb |
| Descriptor | Histone deacetylase 6, POTASSIUM ION, ZINC ION, ... (5 entities in total) |
| Functional Keywords | hdac6, inhibitor, deacetylation, cytosolic protein |
| Biological source | Danio rerio (zebrafish) |
| Total number of polymer chains | 2 |
| Total formula weight | 81651.05 |
| Authors | |
| Primary citation | Ripa, L.,Cassani, C.,Hughes, G.,Ranieri, B.,Ullah, V.,Zambelloni, R.,Andreasson, T.,Collins, M.,Lindberg, B.,Llinas, A.,Pehrson, R.,Barylyuk, K.,Johansson, J.,Ek, M.,Gunnarsson, A.,Jung, B.,Lundqvist, S.,Noven, A.,Sandmark, J.,Astrand, A. Discovery of a Selective Histone Deacetylase 6 Degrader (HDAC6 PROTAC) with a Short and Rigid Linker Demonstrating Sustained Knockdown of HDAC6 In Vivo. Acs Med.Chem.Lett., 17:1294-1302, 2026 Cited by PubMed Abstract: Histone deacetylase 6 (HDAC6) is a cytosolic enzyme that regulates protein acetylation and contributes to the pathogenesis of various lung diseases. We report the discovery and characterization of a novel HDAC6 degrader, compound , designed by conjugating a selective hydroxamic acid HDAC6 inhibitor () to a cereblon-recruiting ligand via a short, rigid linker. Compound exhibited selective HDAC6 degradation with subnanomolar degradation potency in bronchial epithelium cells, effectively inducing α-tubulin hyperacetylation without affecting histone-3 acetylation. In mice, subcutaneous administration achieved high bioavailability (65%) and sustained HDAC6 knockdown in lung tissue for up to 96 h after a single dose, repeated dosing further enhanced degradation and α-tubulin acetylation. Safety and secondary pharmacology profiling confirmed a favorable preclinical safety and selectivity profile. These findings established compound as a potent, selective HDAC6 degrader suitable as a starting point and tool for studying HDAC6-related diseases in the lung epithelium and beyond. PubMed: 42305196DOI: 10.1021/acsmedchemlett.6c00086 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.98 Å) |
Structure validation
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