9ZPA

KRAS G12V Mutant in Complex with GDP and Compound 12.

This is a non-PDB format compatible entry.

Summary for 9ZPA

• Entry DOI: 10.2210/pdb9zpa/pdb
• Descriptor: Isoform 2B of GTPase KRas, MAGNESIUM ION, (10R,14S,21P)-3,25-difluoro-16-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-23-hydroxy-10-methyl-5,6,10,11,12,13-hexahydro-4H-10,14-methano-21,18-(metheno)naphtho[1,8-no]pyrimido[4,5-i][1,3,8,12]oxatriazacyclononadecin-8(9H)-one, ... (6 entities in total)
• Functional Keywords: monomeric, gtpase, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 41344.32

Authors

DiDonato, M.,Spraggon, G. (deposition date: 2025-12-16, release date: 2026-06-03)

Primary citation

Phillips, D.P.,Alper, P.B.,Cho, C.Y.,Borkin, D.,Han, D.,Kochanek, S.E.,Vidal-Biggart, A.,Herath, A.,Gurjar, J.,Lu, W.,Mathison, C.J.N.,Nelson, J.M.,Pei, W.,Yan, S.,Nguyen, B.N.,Hoffman, T.,Okram, B.,Nguyen, T.N.,Jiang, S.,Masick, B.T.,Wang, Z.,Nikulin, V.,Yin, H.,Chen, Y.,Juarez, J.,Sarkisova, Y.,Jia, Y.,Zhou, V.,Liu, G.,Liu, X.,Lu, M.,Taylor, B.L.,Huynh, L.,Wang, Y.,Pacoma, R.,Baaten, J.,Topolewski, K.,Wright, C.,Nguyen, T.,Knee, D.A.,Liu, Q.,Liu, J.,Li, J.,Virata, C.,Briones, S.,DiDonato, M.,Bursulaya, B.,Jones, D.H.,Witmer, D.,Chu, C.,Jin, H.,Richmond, W.,Westling, L.,Hollenbeck, T.,Chong, A.,Franey, S.,Groessl, T.,Shapiro, M.,Effenberger, K.,Arroyo, K.,Bretz, A.,Honda, A.,Brown, J.,Sanchez, C.C.,Gordon, W.P.,Matzen, J.T.,Osterman, N.,Cotesta, S.,Brachmann, S.M.,Wilcken, R.,Zecri, F.,Beyer, K.S.,Molteni, V.,Haling, J.R.
Targeting Multiple KRAS Mutations with High-Affinity Macrocyclic Inhibitors: From Discovery to Preclinical Validation.
J.Med.Chem., 2026

PubMed Abstract: The RAS Switch-II pockets' discovery enabled targeting a challenging molecular site. Covalent KRAS inhibitors inspired efforts to find compounds for other KRAS mutations, notably KRAS and KRAS. A macrocyclization strategy led to the identification of an exceptionally potent lead compound . Highly optimized interactions in the pocket yielded strong affinity against KRAS and KRAS, potent inhibition of phospho-ERK in various KRAS mutant cell lines, and tumor regression in mouse xenograft models.

PubMed: 42155964
DOI: 10.1021/acs.jmedchem.6c00127

Experimental method

X-RAY DIFFRACTION (1.68 Å)