Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.
Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.
Cell Chem Biol. 2023 Oct 19;30(10):1191-1210.e20. doi: 10.1016/j.chembiol.2023.07.005. Epub 2023 Aug 8.
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.
KAT6A 及其同源物 KAT6B 是组蛋白赖氨酸乙酰转移酶（HAT），可以乙酰化组蛋白 H3K23，并在多种肿瘤类型中发挥致癌作用，包括乳腺癌，其中 KAT6A 经常扩增/过表达。然而，针对 KAT6A 进行药物靶向以实现治疗益处一直是一个挑战。在这里，我们描述了一种高度有效、选择性和可口服生物利用的 KAT6A/KAT6B 抑制剂 CTx-648（PF-9363）的鉴定，该抑制剂源自苯并异恶唑系列，在 KAT6A 过表达的乳腺癌中，与 H3K23Ac 抑制相关，表现出抗肿瘤活性。转录组学和表观遗传学研究表明，与 CTx-648 的抗肿瘤活性相关，RNA Pol II 结合减少，与雌激素信号、细胞周期、Myc 和干细胞途径相关的基因下调，这些基因与 CTx-648 在 ER+乳腺癌中的抗肿瘤活性相关。CTx-648 治疗导致 ER+乳腺癌的体内模型中肿瘤生长的强烈抑制，包括对内分泌治疗有抗性的模型，这突出了在 ER+乳腺癌中靶向 KAT6A 的潜力。
