Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

Abstract

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.

• Authors: Shikhar Sharma, Chi-Yeh Chung, Sean Uryu, Jelena Petrovic, Joan Cao, Amanda Rickard, Nataliya Nady, Samantha Greasley, Eric Johnson, Oleg Brodsky, Showkhin Khan, Hui Wang, Zhenxiong Wang, Yong Zhang, Konstantinos Tsaparikos, Lei Chen, Anthony Mazurek, John Lapek, Pei-Pei Kung, Scott Sutton, Paul F Richardson, Eric C Greenwald, Shinji Yamazaki, Rhys Jones, Karen A Maegley, Patrick Bingham, Hieu Lam, Alexandra E Stupple, Aileen Kamal, Anderly Chueh, Anthony Cuzzupe, Benjamin J Morrow, Bin Ren, Catalina Carrasco-Pozo, Chin Wee Tan, Dharmesh D Bhuva, Elizabeth Allan, Elliot Surgenor, François Vaillant, Havva Pehlivanoglu, Hendrik Falk, James R Whittle, Janet Newman, Joseph Cursons, Judy P Doherty, Karen L White, Laura MacPherson, Mark Devlin, Matthew L Dennis, Meghan K Hattarki, Melanie De Silva, Michelle A Camerino, Miriam S Butler, Olan Dolezal, Patricia Pilling, Richard Foitzik, Paul A Stupple, H Rachel Lagiakos, Scott R Walker, Soroor Hediyeh-Zadeh, Stewart Nuttall, Sukhdeep K Spall, Susan A Charman, Theresa Connor, Thomas S Peat, Vicky M Avery, Ylva E Bozikis, Yuqing Yang, Ming Zhang, Brendon J Monahan, Anne K Voss, Tim Thomas, Ian P Street, Sarah-Jane Dawson, Mark A Dawson, Geoffrey J Lindeman, Melissa J Davis, Jane E Visvader, Thomas A Paul
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 30 Issue 10 Pg. 1191-1210.e20 (10 19 2023) ISSN: 2451-9448 [Electronic] United States
• PMID: 37557181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Histones
• Histone Acetyltransferases
• KAT6A protein, human
• KAT6B protein, human

Topics

• Humans
• Female
• Breast Neoplasms (genetics)
• Histones (metabolism)
• Histone Acetyltransferases (genetics, metabolism)
• Signal Transduction
• Cell Line, Tumor