发现了一种高效、选择性、口服可利用的KAT6A/B组蛋白乙酰转移酶抑制剂，对KAT6A高表达的ER+乳腺癌具有疗效。
Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.
发表日期：2023 Aug 08
作者：
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
来源：
Cell Chemical Biology
摘要：
KAT6A和它的拟原型KAT6B是组蛋白赖氨酸乙酰转移酶（HAT），可乙酰化组蛋白H3K23并在包括乳腺癌在内的多种肿瘤类型中发挥致癌作用，其中KAT6A经常被扩增/过表达。然而，药物靶向KAT6A以获得治疗效益一直存在挑战。在本文中，我们描述了一种源自苯并异喹唑系列的高效、选择性和口服生物利用度的KAT6A/KAT6B抑制剂CTx-648（PF-9363），该抑制剂显示出与H3K23Ac抑制在KAT6A过表达的乳腺癌中抗肿瘤活性相关。转录和表观遗传学研究显示CTx-648抗肿瘤活性与ER阳性（ER+）乳腺癌中与雌激素信号传导、细胞周期、Myc和干细胞途径相关的基因的RNA Pol II结合减少和下调有关。CTx-648治疗导致ER+乳腺癌体内模型中肿瘤生长强力抑制，包括对内分泌治疗难治性模型，凸显了靶向KAT6A在ER+乳腺癌中的潜力。版权所有 © 2023 作者. 由 Elsevier Ltd. 出版。保留所有权利。
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.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.