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, Giao N. Hoang, L. Z. Zhao, Robert Susick, Fenglei Zhang, Cheng‐Tsung Lai, Abdellah Allali Hassani, L.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
Abstract
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 23 ( INCB159020 ), 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.