PI3Kα is a lipid kinase that phosphorylates PIP2 and generates PIP3. The hyperactive PI3Kα mutation, H1047R, accounts for about 14% of breast cancer, making it a highly attractive target for drug discovery. Here, we report the cryo-EM structures of PI3Kα^H1047R bound to two different allosteric inhibitors QR-7909 and QR-8557 at a global resolution of 2.7 Å and 3.0 Å, respectively. The structures reveal two distinct binding pockets on the opposite sides of the activation loop. Structural and MD simulation analyses show that the allosteric binding of QR-7909 and QR-8557 inhibit PI3Kα^H1047R hyper-activity by reducing the fluctuation and mobility of the activation loop. Our work provides a strong rational basis for a further optimization and development of highly selective drug candidates to treat PI3Kα^H1047R-driven cancers.

PI3Kα 是一种脂质激酶，可磷酸化 PIP2 并生成 PIP3。高度活跃的 PI3Kα 突变 H1047R 约占乳腺癌的 14%，使其成为极具吸引力的药物发现靶点。在这里，我们报告了 PI3Kα ^H1047R与两种不同变构抑制剂 QR-7909 和 QR-8557 结合的冷冻电镜结构，全局分辨率分别为 2.7 Å 和 3.0 Å。该结构在激活环的相对两侧显示出两个不同的结合袋。结构和 MD 模拟分析表明，QR-7909 和 QR-8557 的变构结合通过降低激活环的波动和移动性来抑制 PI3Kα ^H1047R过度活跃。我们的工作为进一步优化和开发用于治疗 PI3Kα ^H1047R驱动的癌症的高选择性候选药物提供了强有力的合理基础。