6OIQ

Crystal structure of MYST acetyltransferase domain in complex with inhibitor 63

Summary for 6OIQ

• Entry DOI: 10.2210/pdb6oiq/pdb
• Descriptor: Histone acetyltransferase KAT8, ZINC ION, 2-fluoro-N'-(phenylsulfonyl)[1,1'-biphenyl]-3-carbohydrazide, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, myst, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32667.96

Authors

Hermans, S.J.,Chung, M.C.,Parker, M.W.,Thomas, T.,Baell, J.B. (deposition date: 2019-04-09, release date: 2019-07-03, Last modification date: 2024-10-23)

Primary citation

Leaver, D.J.,Cleary, B.,Nguyen, N.,Priebbenow, D.L.,Lagiakos, H.R.,Sanchez, J.,Xue, L.,Huang, F.,Sun, Y.,Mujumdar, P.,Mudududdla, R.,Varghese, S.,Teguh, S.,Charman, S.A.,White, K.L.,Katneni, K.,Cuellar, M.,Strasser, J.M.,Dahlin, J.L.,Walters, M.A.,Street, I.P.,Monahan, B.J.,Jarman, K.E.,Sabroux, H.J.,Falk, H.,Chung, M.C.,Hermans, S.J.,Parker, M.W.,Thomas, T.,Baell, J.B.
Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A.
J.Med.Chem., 62:7146-7159, 2019

PubMed Abstract: A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC of 1.0 μM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (), a highly potent inhibitor of KAT6A (IC = 0.008 μM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.

PubMed: 31256587
DOI: 10.1021/acs.jmedchem.9b00665

Experimental method

X-RAY DIFFRACTION (1.75 Å)