Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents
Daniel L Priebbenow, David J Leaver, Nguyen Nghi, Benjamin Cleary, 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, David M Shackleford, Kasiram Katneni, Matthew Cuellar, Jessica M Strasser, Jayme L Dahlin Show all
JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 2020
A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered..View full abstract
Awarded by National Health and Medical Research Council of Australia (NHMRC)
The National Health and Medical Research Council of Australia (NHMRC) is thanked for research support (#1030704 and #1080146) and fellowship support for J.B. (2012-2016 Senior Research Fellowship #1020411, 2017 - Principal Research Fellowship #1117602). Acknowledged are the Australian Federal Government Education Investment Fund Super Science Initiative and Victorian State Government, Victoria Science Agenda Investment Fund for infrastructure support, and the facilities and scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF), Monash Institute of Pharmaceutical Sciences (MIPS). ATMCF is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. This research was undertaken in part using the MX1 and MX2 beamlines at the Australian Synchrotron, part of ANSTO. We thank the beamline staff for their assistance. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent's Institute is gratefully acknowledged. M.W.P. is a National Health and Medical Research Council of Australia research fellow.