Mirati Therapeutics, 3545 Cray Court, San Diego, California 92121, United States.
J Med Chem. 2024 Mar 28;67(6):4936-4949. doi: 10.1021/acs.jmedchem.4c00078. Epub 2024 Mar 13.
The H1047R mutation of is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3Kα over PI3Kα is crucial due to the role that PI3Kα plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3Kα-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3Kα with high selectivity over PI3Kα, resulting in the discovery of compound . When dosed in the HCC1954 tumor model in mice, provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3Kα including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.
是一种高度普遍存在于乳腺癌和其他实体瘤中的突变。选择性靶向 PI3Kα 而不是 PI3Kα 至关重要，因为 PI3Kα 在正常细胞过程中发挥作用，包括葡萄糖稳态。目前，只有一种 PI3Kα 选择性抑制剂已进入临床试验阶段，而三种 pan 突变（H1047R、H1047L、H1047Y、E542K 和 E545K）选择性 PI3Kα 抑制剂也已进入临床阶段。在这里，我们报告了一系列吡啶并嘧啶酮的设计和发现，这些抑制剂对 PI3Kα 具有高度选择性，对 PI3Kα 的抑制作用很强，从而发现了化合物 。当在 HCC1954 肿瘤模型的小鼠中进行给药时， 提供了肿瘤消退和明显的药效反应。获得了来自几种 PI3Kα 抑制剂的 X 射线共晶结构，揭示了 PI3Kα 中的三种不同结合模式，包括激酶结构域 C 末端中先前报道的隐蔽口袋，其中我们观察到与 Arg1047 的配体诱导相互作用。
