Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A

David J Leaver; Benjamin Cleary; Nghi Nguyen; Daniel L Priebbenow; H Rachel Lagiakos; Julie Sanchez; Lian Xue; Fei Huang; Yuxin Sun; Prashant Mujumdar; Ramesh Mudududdla; Swapna Varghese; Silvia Teguh; Susan A Charman; Karen L White; Kasiram Katneni; Matthew Cuellar; Jessica M Strasser; Jayme L Dahlin; Michael A Walters; Ian P Street; Brendon J Monahan; Kate E Jarman; Helene Jousset Sabroux; Hendrik Falk; Matthew C Chung; Stefan J Hermans; Michael W Parker; Tim Thomas; Jonathan B Baell

doi:10.1021/acs.jmedchem.9b00665

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. Epub 2019 Jul 17.

Authors

David J Leaver, Benjamin Cleary, Nghi Nguyen, Daniel L Priebbenow, H Rachel Lagiakos¹, Julie Sanchez^{2

3}, Lian Xue⁴, Fei Huang⁴, Yuxin Sun, Prashant Mujumdar, Ramesh Mudududdla, Swapna Varghese, Silvia Teguh, Susan A Charman, Karen L White, Kasiram Katneni, Matthew Cuellar⁵, Jessica M Strasser⁵, Jayme L Dahlin⁶, Michael A Walters⁵, 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 Chung⁷, Stefan J Hermans⁷, Michael W Parker⁷, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzenesulfonates / chemistry*
Benzenesulfonates / pharmacology
Caco-2 Cells
Drug Discovery / methods*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Histone Acetyltransferases / antagonists & inhibitors*
Histone Acetyltransferases / metabolism*
Humans
Hydrazines / chemistry*
Hydrazines / pharmacology
Mice
Protein Structure, Secondary

Substances

(1,1'-Biphenyl)-3-carboxylic acid, 4-fluoro-5-methyl-, 2-(phenylsulfonyl)hydrazide
Benzenesulfonates
Enzyme Inhibitors
Hydrazines
Histone Acetyltransferases
KAT6A protein, human