首创性药物索托拉西的研制启示

Enlightenment from the creation of the first-in-class drug sotorasib

2021年5月,美国FDA批准了安进公司研制的抗肿瘤药物索托拉西上市,成为全球第一个治疗携带有KRAS^(G12C)变异的中晚期非小细胞肺癌患者的靶向药物。大约30%的人类肿瘤发生KRAS^(G12C)的变异,被称作肿瘤发生和发展的永动机。尽管KRAS变异与肿瘤的密切相关已知近40年,但以KRAS为靶标研制药物的成效甚小。索托拉西的批准上市是个划时代的突破,颠覆了非可药性靶标难以成药的固有偏见。构建分子结构作为新药研发链的最关键的环节,本文从药物化学视角解读安进公司的科学家成功之路,揭示其创新理念以及如何娴熟地运用药物研究中的各种平台技术,使国内新药研发人员从中得到有益的启示。

The US FDA approved the anti-tumor drug sotorasib developed by Amgen in May 2021, which becomes the first targeted drug worldwide for the treatment of patients with advanced non-small cell lung cancer with KRAS^(G12C) mutations. KRAS^(G12C) mutations occur in approximately 30% of human tumors, called perpetual motion machines for tumorigenesis and development. Despite knowing the close relationship between KRAS mutations and tumors, nearly four decades of efforts have failed to identify clinically useful inhibitors of the KRAS protein. The approval of sotorasib on the market is an epoch-making breakthrough overturning the inherent prejudice that undruggable targets are impossible to make medicines. The construction of molecular structure is the most critical link in the R&D chain of new drugs. This article attempts to interpret the success of Amgen’s scientists from the perspective of medicinal chemistry, reveal their innovation ideas, and skillfully use various platform technologies in drug research, and hopefully gains the useful enlightenment from it.