Ye Qinda, Shvartsbart Artem, Li Zhenwu, Gan Pei, Policarpo Rocco L, Qi Chao, Roach Jeremy J, Zhu Wenyu, McCammant Matthew S, Hu Bin, Li Gencheng, Yin Haolin, Carlsen Peter, Hoang Gia, Zhao Le, Susick Robert, Zhang Fenglei, Lai Cheng-Tsung, Allali Hassani Abdellah, Epling Leslie B, Gallion Alexandra, Kurzeja-Lipinski Kerri, Gallagher Karen, Roman Valerie, Farren Matthew R, Kong Weixi, Deller Marc C, Zhang Guofeng, Covington Maryanne, Diamond Sharon, Kim Sunkyu, Yao Wenqing, Sokolsky Alexander, Wang Xiaozhao
Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Department of Computational Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
J Med Chem. 2025 Jan 23;68(2):1924-1939. doi: 10.1021/acs.jmedchem.4c02662. Epub 2025 Jan 8.
The inhibition of mutant KRAS proteins has emerged as a promising approach for treating KRAS-driven cancers, as evidenced by the clinical success of KRAS G12C inhibitors. KRAS G12D, the most common mutant, promises significant expansion of the addressable patient population; however, the reduced nucleophilicity of aspartate compared to cysteine poses significant challenges in balancing sufficient potency with ADME properties to support oral exposure. Herein, we describe the discovery of KRAS G12D inhibitor (), which achieves oral exposure in nonhuman primate (NHP). Starting from a weakly potent hit, structure-based drug design was utilized to drive significant potency. Focus on molecular rigidity and balanced polarity then allowed for successful optimization of properties required for oral exposure.
抑制突变型KRAS蛋白已成为治疗KRAS驱动型癌症的一种有前景的方法，KRAS G12C抑制剂的临床成功证明了这一点。KRAS G12D是最常见的突变体，有望显著扩大可治疗患者群体；然而，与半胱氨酸相比，天冬氨酸的亲核性降低，这在平衡足够的效力与支持口服给药的药物代谢动力学（ADME）性质方面带来了重大挑战。在此，我们描述了KRAS G12D抑制剂（）的发现，该抑制剂在非人类灵长类动物（NHP）中实现了口服给药。从一个效力较弱的先导化合物开始，利用基于结构的药物设计来提高效力。然后专注于分子刚性和平衡极性，从而成功优化了口服给药所需的性质。
