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

Sharma, S; Chung, CY; Uryu, S; Petrovic, J; Cao, J; Rickard, A; Nady, N; Greasley, S; Johnson, E; Brodsky, O; Khan, S; Wang, H; Wang, Z; Zhang, Y; Tsaparikos, K; Chen, L; Mazurek, A; Lapek, J; Kung, PP; Sutton, S; Richardson, PF; Greenwald, EC; Yamazaki, S; Jones, R; Maegley, KA; Bingham, P; Lam, H; Stupple, AE; Kamal, A; Chueh, A; Cuzzupe, A; Morrow, BJ; Ren, B; Carrasco-Pozo, C; Tan, CW; Bhuva, DD; Allan, E; Surgenor, E; Vaillant, F; Pehlivanoglu, H; Falk, H; Whittle, JR; Newman, J; Cursons, J; Doherty, JP; White, KL; MacPherson, L; Devlin, M; Dennis, ML; Hattarki, MK; De Silva, M; Camerino, MA; Butler, MS; Dolezal, O; Pilling, P; Foitzik, R; Stupple, PA; Lagiakos, HR; Walker, SR; Hediyeh-Zadeh, S; Nuttall, S; Spall, SK; Charman, SA; Connor, T; Peat, TS; Avery, VM; Bozikis, YE; Yang, Y; Zhang, M; Monahan, BJ; Voss, AK; Thomas, T; Street, IP; Dawson, SJ; Dawson, MA; Lindeman, GJ; Davis, MJ; Visvader, JE; Paul, TA

Author(s): Sharma, S; Chung, CY; Uryu, S; Petrovic, J; Cao, J; Rickard, A; Nady, N; Greasley, S; Johnson, E; Brodsky, O; Khan, S; Wang, H; Wang, Z; Zhang, Y; Tsaparikos, K; Chen, L; Mazurek, A; Lapek, J; Kung, PP; Sutton, S; Richardson, PF; Greenwald, EC; Yamazaki, S; Jones, R; Maegley, KA; Bingham, P; Lam, H; Stupple, AE; Kamal, A; Chueh, A; Cuzzupe, A; Morrow, BJ; Ren, B; Carrasco-Pozo, C; Tan, CW; Bhuva, DD; Allan, E; Surgenor, E; Vaillant, F; Pehlivanoglu, H; Falk, H; Whittle, JR; Newman, J; Cursons, J; Doherty, JP; White, KL; MacPherson, L; Devlin, M; Dennis, ML; Hattarki, MK; De Silva, M; Camerino, MA; Butler, MS; Dolezal, O; Pilling, P; Foitzik, R; Stupple, PA; Lagiakos, HR; Walker, SR; Hediyeh-Zadeh, S; Nuttall, S; Spall, SK; Charman, SA; Connor, T; Peat, TS; Avery, VM; Bozikis, YE; Yang, Y; Zhang, M; Monahan, BJ; Voss, AK; Thomas, T; Street, IP; Dawson, SJ; Dawson, MA; Lindeman, GJ; Davis, MJ; Visvader, JE; Paul, TA;
Details: Publication Year 2023-10-19,Volume 30,Issue #10,Page 1191-1210.e20
Journal Title: Cell Chemical Biology
Publication Type: Research article
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.
Publisher: Cell Press
Keywords: CTx-648; Kat6a; Kat6b; Pf-9363; breast cancer; cell cycle; epigenetics; estrogen receptor; resistance
Department(s): Laboratory Research; Medical Oncology; Clinical Haematology; Familial Cancer Centre
PubMed ID: 37557181
Publisher's Version: https://doi.org/10.1016/j.chembiol.2023.07.005
Open Access at Publisher's Site: https://doi.org/10.1016/j.chembiol.2023.07.005
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-14 12:41:54

Last Modified: 2023-11-14 12:43:26