9Y1X

Crystal structure of NRas-G12D in complex with GDP and IACS-56676

This is a non-PDB format compatible entry.

Summary for 9Y1X

• Entry DOI: 10.2210/pdb9y1x/pdb
• Related: 9Y0G
• Descriptor: GTPase NRas, GUANOSINE-5'-DIPHOSPHATE, N-({(6P)-6-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-3-[(1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl]-1,4-dicyclopropyl-7-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl}methyl)acetamide, ... (6 entities in total)
• Functional Keywords: inhibitor, gtpase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 41097.30

Authors

Johnson, T.A.,Cross, J.B. (deposition date: 2025-08-31, release date: 2026-02-25, Last modification date: 2026-03-04)

Primary citation

Cox, J.B.,Nair, V.,Mandal, P.,Reyna, N.,Tran, T.,Mustachio, L.M.,Bardenhagen, J.,Fawver, J.,Shepard, H.,Hickey, A.M.,Wu, Q.,Rodriguez, C.,Yu, F.,Phan, P.,Mendiola, A.J.,Johnson, R.,Thapar, R.,Johnson, T.,Jiang, Y.,Cross, J.B.,Do, M.K.G.,Jones, P.,Marsalek, J.,Heffernan, T.,Soth, M.J.,Nagy, E.
Structure-Guided Development of NRAS G12D Inhibitors Based on a 5‐Azaindole Core.
Acs Med.Chem.Lett., 17:425-432, 2026

PubMed Abstract: NRAS G12D mutations are predominantly found in melanoma and hematologic malignancies, and there is an unmet need for developing targeted therapies against this oncogene. Herein, we describe the structure-guided development of IACS-56676, a selective and potent NRAS G12D inhibitor useful as a tool compound for further studies of NRAS biology. The development process revealed key insights into gaining selectivity between NRAS and KRAS proteins. Notably, stabilization of the p-loop and substitution toward Leu 95 while maintaining key interactions with Asp12, Gly60, and Asp69 improved NRAS G12D potency and resulted in selectivity against wild-type KRAS/non-responder.

PubMed: 41704364
DOI: 10.1021/acsmedchemlett.5c00647

Experimental method

X-RAY DIFFRACTION (1.72 Å)