9NZM

Crystal Structure of Kirsten Rat Sarcoma G12C Complexed with GMPPNP and Covalently Bound to an Adduct of {(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-[(2Z)-2-fluoro-3-(pyridin-2-yl)prop-2-enoyl]piperazin-2-yl}acetonitrile

This is a non-PDB format compatible entry.

Summary for 9NZM

• Entry DOI: 10.2210/pdb9nzm/pdb
• Related: 9NZN
• Descriptor: Isoform 2B of GTPase KRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, {(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-[(3R)-3-fluoro-3-(pyridin-2-yl)propanoyl]piperazin-2-yl}acetonitrile, ... (5 entities in total)
• Functional Keywords: kras, gtpase, inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 41445.57

Authors

Sheriff, S.,Pokross, M.,Witmer, M. (deposition date: 2025-04-01, release date: 2025-11-05, Last modification date: 2026-03-18)

Primary citation

Condakes, M.L.,Zhang, Z.,Danahy, D.B.,Moore, R.R.,Lakkaraju, S.K.,Zhuo, X.,Amako, Y.,Borzilleri, R.M.,Balachander, S.B.,Chourb, L.,Civiello, R.L.,Dongre, A.R.,Downes, D.P.,Drexler, D.M.,Dudiak, B.M.,Dzhekieva, L.,El-Samin, M.,Fink, B.E.,Frederick, K.,Huang, C.,Khan, J.,Lees, E.,Levins, C.G.,McCarthy, C.,Mintier, G.A.,Mosure, K.,Parker, M.F.,Powles, R.,Qi, J.,Ruzanov, M.,Sharma, S.,Sheriff, S.,Singh, A.K.,Stedman, J.,Szapiel, N.,Thompson, R.L.,Vaccaro, W.,Wang, T.,Yang, T.,You, D.,Meyer, M.J.,Bronson, J.J.,Stewart, M.L.
Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C.
Nat Commun, 17:-, 2026

PubMed 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.

PubMed: 41620418
DOI: 10.1038/s41467-026-69003-0

Experimental method

X-RAY DIFFRACTION (1.586 Å)