Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor

J Med Chem. 2025 Jan 23;68(2):1924-1939. doi: 10.1021/acs.jmedchem.4c02662.

Qinda Ye ¹, Artem Shvartsbart ¹, Zhenwu Li ¹, Pei Gan ¹, Rocco L Policarpo ¹, Chao Qi ¹, Jeremy J Roach ¹, Wenyu Zhu ¹, Matthew S McCammant ¹, Bin Hu ¹, Gencheng Li ¹, Haolin Yin ¹, Peter Carlsen ¹, Gia Hoang ¹, Le Zhao ¹, Robert Susick ¹, Fenglei Zhang ¹, Cheng-Tsung Lai ², Abdellah Allali Hassani ³, Leslie B Epling ³, Alexandra Gallion ⁴, Kerri Kurzeja-Lipinski ³, Karen Gallagher ³, Valerie Roman ⁴, Matthew R Farren ⁴, Weixi Kong ⁵, Marc C Deller ³, Guofeng Zhang ³, Maryanne Covington ³, Sharon Diamond ⁵, Sunkyu Kim ⁴, Wenqing Yao ¹ ⁴, Alexander Sokolsky ¹, Xiaozhao Wang ¹

Affiliations

1 Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
2 Department of Computational Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
3 Department of Applied Technology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
4 Department of Preclinical Pharmacology, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.
5 Department of DMB, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803, United States.

PMID: 39772605 DOI: 10.1021/acs.jmedchem.4c02662

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-168847

INCB159020

KRAS G12D Inhibitor

Ras

Cancer

Name
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