Discovery of INCB161734: A Selective Inhibitor of the KRAS G12D Mutant
Abstract The discovery of the clinical KRAS G12D inhibitor INCB161734 is described. Starting from a previously disclosed orally bioavailable tool compound 1, a concerted effort to improve the predicted human dose via modulation of potency and pharmacokinetics was undertaken. Careful consideration of the metabolic profile was key to designing low clearance compounds. In addition, the molecular size and fraction sp3 character were carefully controlled to improve permeability and crystalline solubility. From this effort, INCB161734 was identified as a balanced compound with excellent oral exposure, potent antiproliferative activity in xenograft tumor models, and excellent selectivity against wild-type K/H/NRAS. INCB161734 is currently undergoing clinical trials in patients with KRAS G12D mutations.
Authors
- Artem Shvartsbart (ORCID: https://orcid.org/0000-0002-1438-3095)
- Pei Gan
- Abdellah Allali‐Hassani
- Keith Kennedy
- Padmaja K Polam
- Leslie B. Epling (ORCID: https://orcid.org/0000-0003-4897-1300)
- Dashyant Dhanak
- Matthew R. Farren (ORCID: https://orcid.org/0000-0001-5510-8869)
- Robert Susick
- Qinda Ye (ORCID: https://orcid.org/0000-0002-7864-1751)
- Jason Boer (ORCID: https://orcid.org/0009-0008-5628-0028)
- Valerie Dostalik Roman
- S. Kim
- Karen Gallagher
- Rocco L. Policarpo (ORCID: https://orcid.org/0000-0001-9819-2394)
- Zhenwu Li (ORCID: https://orcid.org/0000-0003-0962-5931)
- Marc C. Deller (ORCID: https://orcid.org/0000-0001-8070-6502)
- Kerri Kurzeja-Lipinski
- Sean Bowen (ORCID: https://orcid.org/0000-0003-1047-4325)
- Jeremy J. Roach
- Jennifer J. Harris
- Xiaozhao Wang (ORCID: https://orcid.org/0009-0002-0257-4393)
- Wenqing Yao (ORCID: https://orcid.org/0009-0004-0369-4623)
- Alexander Sokolsky (ORCID: https://orcid.org/0000-0001-9974-8948)
- Alexandra Gallion
- Maryanne B. Covington
- Wenyu Zhu
- Peter Carlsen
- Matthew S. McCammant (ORCID: https://orcid.org/0009-0006-9961-2796)
- Guofeng Zhang (ORCID: https://orcid.org/0000-0001-9675-2044)
- Hui Wang
- Le Zhao
- Chengtsung Lai
- Weixi Kong
- Gia Hoang
- Bin Hu
- Haolin Yin
- Chao Qi
- Chunyin Law
- Fenglei Zhang
- Gencheng Li
Institutions
- Incyte (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c02625
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Incyte