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

Article

Author: Cursons, Joseph ; De Silva, Melanie ; Khan, Showkhin ; Rickard, Amanda ; Greenwald, Eric C ; Lam, Hieu ; Cuzzupe, Anthony ; Zhang, Ming ; Dolezal, Olan ; Brodsky, Oleg ; Dawson, Mark A ; Davis, Melissa J ; White, Karen L ; Walker, Scott R ; Mazurek, Anthony ; Paul, Thomas A ; Bozikis, Ylva E ; Whittle, James R ; Nuttall, Stewart ; Wang, Hui ; Maegley, Karen A ; Nady, Nataliya ; Dawson, Sarah-Jane ; Richardson, Paul F ; Lagiakos, H Rachel ; Street, Ian P ; Voss, Anne K ; Monahan, Brendon J ; Zhang, Yong ; Cao, Joan ; Tsaparikos, Konstantinos ; Kung, Pei-Pei ; Surgenor, Elliot ; Wang, Zhenxiong ; Petrovic, Jelena ; Lapek, John ; Morrow, Benjamin J ; Vaillant, François ; Stupple, Alexandra E ; Connor, Theresa ; Jones, Rhys ; Pehlivanoglu, Havva ; Uryu, Sean ; Doherty, Judy P ; Falk, Hendrik ; Avery, Vicky M ; Greasley, Samantha ; Yang, Yuqing ; Pilling, Patricia ; Tan, Chin Wee ; Chen, Lei ; Chung, Chi-Yeh ; Ren, Bin ; Peat, Thomas S ; Spall, Sukhdeep K ; Carrasco-Pozo, Catalina ; Visvader, Jane E ; Sutton, Scott ; Charman, Susan A ; Hediyeh-Zadeh, Soroor ; Chueh, Anderly ; Sharma, Shikhar ; Devlin, Mark ; Butler, Miriam S ; Bhuva, Dharmesh D ; Camerino, Michelle A ; Newman, Janet ; Yamazaki, Shinji ; MacPherson, Laura ; Kamal, Aileen ; Bingham, Patrick ; Johnson, Eric ; Dennis, Matthew L ; Lindeman, Geoffrey J ; Thomas, Tim ; Foitzik, Richard ; Hattarki, Meghan K ; Stupple, Paul A ; Allan, Elizabeth

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.

01 Oct 2023·Cell Chemical Biology

HATS off to KAT6A/B inhibitors: A new way to target estrogen-receptor-positive breast cancer

Article

Author: Jeselsohn, Rinath ; Polyak, Kornelia

Inhibitors for the KAT6 family of histone acetyltransferases (HATs) have been actively pursued due to the oncogenic roles of KAT6A in human cancer. CTx-648 is a novel KAT6A/B inhibitor with excellent pharmacokinetic properties and in vivo efficacy that represents a promising new treatment strategy for estrogen-receptor-positive breast cancer.

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Indication	Highest Phase	Country/Location	Organization	Date
Estrogen receptor positive breast cancer	Preclinical	US	Pfizer Inc.	08 Aug 2023

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