9Y0G

Crystal structure of NRas-G12D in complex with GDP and compound 1

This is a non-PDB format compatible entry.

Summary for 9Y0G

• Entry DOI: 10.2210/pdb9y0g/pdb
• Descriptor: GTPase NRas, GUANOSINE-5'-DIPHOSPHATE, (5P)-3-chloro-4-cyclopropyl-5-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(4s,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)phenol, ... (6 entities in total)
• Functional Keywords: inhibitor, gtpase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 40538.38

Authors

Johnson, T.A.,Cross, J.B. (deposition date: 2025-08-28, 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 (1.8 Å)