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
  • 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.