Nearly a century after its first description, configurationally stable axial chirality remains a rare feature in marketed drugs. In the development of the KRAS^G12C inhibitor sotorasib (LUMAKRAS/LUMYKRAS), an axially chiral biaryl moiety proved a critical structural element in engaging a “cryptic” protein binding pocket and enhancing inhibitor potency. Restricted rotation about this axis of chirality gave rise to configurationally stable atropisomers that demonstrated a 10-fold difference in potency. The decision to develop sotorasib as a single-atropisomer drug gave rise to a range of analytical and synthetic challenges, whose resolution we review here.

中文翻译：

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解决 KRAS G12C 共价抑制剂 Sotorasib 开发中的阻转异构现象：结构、分析和合成方面的考虑

在首次描述近一个世纪后，构型稳定的轴向手性仍然是市售药物中的罕见特征。在 KRAS ^G12C抑制剂 sotorasib (LUMAKRAS/LUMYKRAS) 的开发过程中，轴向手性联芳基部分被证明是参与“隐蔽”蛋白质结合口袋和增强抑制剂效力的关键结构元素。围绕该手性轴的受限旋转产生了构型稳定的阻转异构体，其效力相差 10 倍。将 sotorasib 开发为单一阻转异构体药物的决定引发了一系列分析和合成挑战，我们在此回顾了这些挑战的解决方案。