2. Academic Validation
  3. Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C

Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C

  • Nat Commun. 2026 Jan 31;17(1):2233. doi: 10.1038/s41467-026-69003-0.
Matthew L Condakes 1,  Zhuo Zhang 2,  Derek B Danahy 2,  Richard R Moore 2,  Sirish Kaushik Lakkaraju 3,  Xiaoliang Zhuo 2,  Yuka Amako 2,  Robert M Borzilleri 3,  Srividya B Balachander 2,  Lisa Chourb 2,  Rita L Civiello 2,  Ashok R Dongre 2,  Daniel P Downes 3,  Dieter M Drexler 2,  Brianne M Dudiak 2,  Liudmila Dzhekieva 3,  Miriam El-Samin 2,  Brian E Fink 3,  Kosea Frederick 2,  Cherrie Huang 2,  Javed Khan 3,  Emma Lees 2,  Christopher G Levins 3,  Courtney McCarthy 2,  Gabriel A Mintier 3,  Katherine Mosure 2,  Michael F Parker 2,  Ryan Powles 2,  Jie Qi 2,  Max Ruzanov 3,  Sanya Sharma 2,  Steven Sheriff 3,  Ashish K Singh 2,  Justin Stedman 2,  Nicolas Szapiel 3,  Rebecca L Thompson 2,  Wayne Vaccaro 3,  Tai Wang 2,  Tianfu Yang 2,  Dan You 2,  Matthew J Meyer 2,  Joanne J Bronson 2,  Michelle L Stewart 4
Affiliations

Affiliations

  • 1 Bristol Myers Squibb, 250 Water St., Cambridge, MA, USA. matthew@condakes.com.
  • 2 Bristol Myers Squibb, 250 Water St., Cambridge, MA, USA.
  • 3 Bristol Myers Squibb, Route 206 & Province Line Rd., Princeton, NJ, USA.
  • 4 Bristol Myers Squibb, 250 Water St., Cambridge, MA, USA. 4michellestewart@gmail.com.
PMID: 41620418 DOI: 10.1038/s41467-026-69003-0
Abstract

The discovery of KRAS G12C inactive state inhibitors represented a significant advancement in the field of precision oncology. While inactive state inhibition shows promise in patients, Switch II (SWII)-binding inhibitors targeting both inactive and active states remain an underdeveloped therapeutic modality. Here, we describe the discovery of such KRAS G12C dual inhibitors that bind the SWII allosteric site using a chemically differentiated warhead to covalently modify both the KRAS G12C inactive and active states. Co-crystal structures reveal that these inhibitors perturb a key water-mediated hydrogen bonding network and trigger allosteric remodeling of the GTP-bound protein surface and SWI that prevents binding to downstream effectors. Consistent with simultaneous targeting of the active and inactive states, dual inhibitors provide rapid covalent target engagement and suppression of MAPK signaling. However, they demonstrate similar efficacy in cellular and in vivo models when compared to inactive state-selective ones despite faster target inactivation. Furthermore, both inhibitor classes show similar cellular efficacy in the presence of growth factors that drive KRAS, wt NRAS, and wt HRAS to the active state. These data provide the first detailed account of targeting both the active and inactive states of KRAS G12C and highlight the absence of a mechanistic advantage in contexts dependent on prolonged target inhibition.

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