2. Academic Validation
  3. Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A

Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A

  • J Med Chem. 2019 Aug 8;62(15):7146-7159. doi: 10.1021/acs.jmedchem.9b00665.
David J Leaver,  Benjamin Cleary,  Nghi Nguyen,  Daniel L Priebbenow,  H Rachel Lagiakos 1,  Julie Sanchez 2 3,  Lian Xue 4,  Fei Huang 4,  Yuxin Sun,  Prashant Mujumdar,  Ramesh Mudududdla,  Swapna Varghese,  Silvia Teguh,  Susan A Charman,  Karen L White,  Kasiram Katneni,  Matthew Cuellar 5,  Jessica M Strasser 5,  Jayme L Dahlin 6,  Michael A Walters 5,  Ian P Street 2 1 3,  Brendon J Monahan 2 1 3,  Kate E Jarman 2 3,  Helene Jousset Sabroux 2 3,  Hendrik Falk 2 1 3,  Matthew C Chung 7,  Stefan J Hermans 7,  Michael W Parker 7,  Tim Thomas 2 3,  Jonathan B Baell 4 8
Affiliations

Affiliations

  • 1 Cancer Therapeutics CRC , 343 Royal Parade , Parkville , Victoria 3052 , Australia.
  • 2 Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade , Parkville , Victoria 3052 , Australia.
  • 3 Department of Medical Biology , University of Melbourne , Parkville , Victoria 3050 , Australia.
  • 4 School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China.
  • 5 Institute for Therapeutics Discovery and Development , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55455 , United States.
  • 6 Department of Pathology , Brigham and Women's Hospital, Boston , 75 Francis Street , Boston , Massachusetts 02115 , United States.
  • 7 ACRF Rational Drug Discovery Centre , St. Vincent's Institute of Medical Research , Fitzroy , Victoria 3065 , Australia.
  • 8 ARC Centre for Fragment-Based Design , Monash University , Parkville , Victoria 3052 , Australia.
PMID: 31256587 DOI: 10.1021/acs.jmedchem.9b00665
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 IC50 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 (IC50 = 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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