Cell chemical biology · 2023

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

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

Аннотация

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.

Предметные рубрики MeSH

Humans Female Breast Neoplasms Histones Histone Acetyltransferases Signal Transduction Cell Line, Tumor

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH