6pde

Crystal structure of MYST acetyltransferase domain in complex with inhibitor 40

spinqualitylabelsall models 6pde, resolution 2.22Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6pde is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.22Å Ligands: ALY, GOL, NA, O9V, SO4, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 muM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 muM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats. Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents.,Priebbenow DL, Leaver DJ, Nguyen N, Cleary B, Lagiakos HR, Sanchez J, Xue L, Huang F, Sun Y, Mujumdar P, Mudududdla R, Varghese S, Teguh S, Charman SA, White KL, Shackleford DM, Katneni K, Cuellar M, Strasser JM, Dahlin JL, Walters MA, Street IP, Monahan BJ, Jarman KE, Jousset Sabroux H, Falk H, Chung MC, Hermans SJ, Downer NL, Parker MW, Voss AK, Thomas T, Baell JB J Med Chem. 2020 Mar 19. doi: 10.1021/acs.jmedchem.9b02071. PMID:32118427 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone acetyltransferase 3D structures

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