Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα

Small
molecule inhibitors that target the phosphatidylinositol
3-kinase (PI3K) signaling pathway have received significant interest
for the treatment of cancers. The class I isoform PI3Kα is most
commonly associated with solid tumors via gene amplification or activating
mutations. However, inhibitors demonstrating both PI3K isoform and
mutant specificity have remained elusive. Herein, we describe the
optimization and characterization of a series of benzoxazepin-oxazolidinone
ATP-competitive inhibitors of PI3Kα which also induce the selective
degradation of the mutant p110α protein, the catalytic subunit
of PI3Kα. Structure-based design informed isoform-specific interactions
within the binding site, leading to potent inhibitors with greater
than 300-fold selectivity over the other Class I PI3K isoforms. Further
optimization of pharmacokinetic properties led to excellent in vivo
exposure and efficacy and the identification of clinical candidate
GDC-0077 (inavolisib, 32), which is now under evaluation
in a Phase III clinical trial as a treatment for patients with PIK3CA-mutant breast cancer.

靶向磷脂酰肌醇3-激酶（phosphatidylinositol 3-kinase, PI3K）信号通路的小分子抑制剂，在癌症治疗领域受到了广泛关注。I型亚型PI3Kα最为常见地通过基因扩增或激活性突变与实体瘤相关联。然而，同时兼具PI3K亚型与突变体特异性的抑制剂始终难以研发成功。本文报道了一系列苯并氧氮卓-恶唑烷酮类PI3Kα ATP竞争性抑制剂的优化与表征工作，这类抑制剂同时可诱导突变型p110α蛋白（PI3Kα的催化亚基）发生选择性降解。基于结构的设计明确了结合位点内的亚型特异性相互作用，由此获得了相较于其他I型PI3K亚型具有300倍以上选择性的强效抑制剂。通过进一步优化药代动力学特性，该类抑制剂获得了优异的体内暴露量与抗肿瘤活性，并最终筛选得到临床候选化合物GDC-0077（inavolisib，编号32），目前该化合物正针对PIK3CA突变型乳腺癌患者开展III期临床试验评估。