9ggk

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 (CD2) in complex with N-((6-(Hydroxyamino)-6-oxohexyl)oxy)-4-(4-methoxyphenyl)thiazole-2-carboxamide

spinqualitylabelsall models 9ggk, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9ggk is a 1 chain structure with sequence from Danio rerio. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.9Å Ligands: A1IK2, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function F8W4B7_DANRE Publication Abstract from PubMed Histone deacetylase inhibitors (HDACi) are established anticancer drugs, especially in hematological cancers. This study aimed to design, synthesize, and evaluate a set of HDACi featuring a pentyloxyamide connecting unit linker region and substituted phenylthiazole cap groups. A structural optimization program yielded HDACi with nanomolar inhibitory activity against histone deacetylase class I/IIb enzymes. The novel inhibitors (4d and 4m) showed superior antileukemic activity compared to several approved HDACi. Furthermore, 4d and 4m displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for 4d with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, 4d demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, 4d effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of 4d and 4m to the catalytic domain 2 of HDAC6 from Danio rerio were determined by X-ray crystallography. Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia.,Fischer F, Schliehe-Diecks J, Tu JW, Gangnus T, Ho YL, Hebeis M, Alves Avelar LA, Scharov K, Watrin T, Kemkes M, Stachura P, Daugs K, Biermann L, Kremeyer J, Horstick N, Span I, Pandyra AA, Borkhardt A, Gohlke H, Kassack MU, Burckhardt BB, Bhatia S, Kurz T J Med Chem. 2024 Nov 27. doi: 10.1021/acs.jmedchem.4c02024. PMID:39602240 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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