6OIN

Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A.

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.

(2019) J Med Chem 62: 7146-7159

• PubMed: 31256587 Search on PubMed
• DOI: https://doi.org/10.1021/acs.jmedchem.9b00665
• Primary Citation of Related Structures:  
  6OIN, 6OIO, 6OIP, 6OIQ, 6OIR


• 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 ₅₀ of 1.0 μM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 ( 97 ), a highly potent inhibitor of KAT6A (IC ₅₀ = 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.

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Organizational Affiliation: 

Cancer Therapeutics CRC , 343 Royal Parade , Parkville , Victoria 3052 , Australia.