2. Academic Validation
  3. Acetyl-Click Screening Platform Identifies Small-Molecule Inhibitors of Histone Acetyltransferase 1 (HAT1)

Acetyl-Click Screening Platform Identifies Small-Molecule Inhibitors of Histone Acetyltransferase 1 (HAT1)

  • J Med Chem. 2023 Apr 27;66(8):5774-5801. doi: 10.1021/acs.jmedchem.3c00039.
Jitender D Gaddameedi 1,  Tristan Chou 2,  Benjamin S Geller 2,  Amithvikram Rangarajan 2 3,  Tarun A Swaminathan 4,  Danielle Dixon 4,  Katherine Long 4,  Caiden J Golder 4,  Van A Vuong 4,  Selene Banuelos 2,  Robert Greenhouse 5,  Michael P Snyder 2,  Andrew M Lipchik 1,  Joshua J Gruber 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48201, United States.
  • 2 Department of Genetics, Stanford University School of Medicine, Stanford, California 94309, United States.
  • 3 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
  • 4 Department of Internal Medicine, Hematology-Oncology Division, Cecil H. and Ida Green Center for Reproductive Biology Sciences, UT Southwestern Medical Center, Dallas, Texas 75235, United States.
  • 5 Department of Otolaryngology, Stanford University School of Medicine, Stanford, California 94309, United States.
PMID: 37027002 DOI: 10.1021/acs.jmedchem.3c00039
Abstract

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H4. To ascertain whether targeting HAT1 is a viable Anticancer treatment strategy, we sought to identify small-molecule inhibitors of HAT1 by developing a high-throughput HAT1 acetyl-click assay. Screening of small-molecule libraries led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity. Compounds were refined by synthesis and testing of over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl side chain improved enzymatic potency and cellular growth suppression. One compound (JG-2016 [24a]) showed relative specificity toward HAT1 compared to Other acetyltransferases, suppressed the growth of human Cancer cell lines, impaired enzymatic activity in cellulo, and interfered with tumor growth. This is the first report of a small-molecule inhibitor of the HAT1 enzyme complex and represents a step toward targeting this pathway for Cancer therapy.

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