Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor.
Qinda Ye, Artem Shvartsbart, Zhenwu Li, Pei Gan, Rocco L Policarpo, Chao Qi, Jeremy J Roach, Wenyu Zhu, Matthew S McCammant, Bin Hu, Gencheng Li, Haolin Yin, Peter Carlsen, Gia Hoang, Le Zhao, Robert Susick, Fenglei Zhang, Cheng-Tsung Lai, Abdellah Allali Hassani, Leslie B Epling, Alexandra Gallion, Kerri Kurzeja-Lipinski, Karen Gallagher, Valerie Roman, Matthew R Farren, Weixi Kong, Marc C Deller, Guofeng Zhang, Maryanne Covington, Sharon Diamond, Sunkyu Kim, Wenqing Yao, Alexander Sokolsky, Xiaozhao Wang
Author Information
Qinda Ye: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Artem Shvartsbart: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Zhenwu Li: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Pei Gan: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Rocco L Policarpo: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Chao Qi: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Jeremy J Roach: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Wenyu Zhu: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Matthew S McCammant: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Bin Hu: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Gencheng Li: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Haolin Yin: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Peter Carlsen: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Gia Hoang: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Le Zhao: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Robert Susick: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Fenglei Zhang: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Cheng-Tsung Lai: Department of Computational Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Abdellah Allali Hassani: Department of Applied Technology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Leslie B Epling: Department of Applied Technology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Alexandra Gallion: Department of Preclinical Pharmacology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Kerri Kurzeja-Lipinski: Department of Applied Technology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Karen Gallagher: Department of Applied Technology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Valerie Roman: Department of Preclinical Pharmacology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Matthew R Farren: Department of Preclinical Pharmacology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Weixi Kong: Department of DMB, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Marc C Deller: Department of Applied Technology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Guofeng Zhang: Department of Applied Technology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Maryanne Covington: Department of Applied Technology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Sharon Diamond: Department of DMB, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Sunkyu Kim: Department of Preclinical Pharmacology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
Wenqing Yao: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
Alexander Sokolsky: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States. ORCID
Xiaozhao Wang: Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
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.
