7RT5

Crystal structure of KRAS G12D with compound 36 (4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(4s,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidine) bound

Summary for 7RT5

• Entry DOI: 10.2210/pdb7rt5/pdb
• Related: 7RPZ
• Descriptor: Isoform 2B of GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, 4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(4s,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidine, ... (5 entities in total)
• Functional Keywords: oncoprotein, g12d, gdp, gtpase, kras4b, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 20398.88

Authors

Gunn, R.J.,Thomas, N.C.,Xiaolun, W.,Lawson, J.D.,Marx, M.A. (deposition date: 2021-08-12, release date: 2021-12-22, Last modification date: 2023-10-18)

Primary citation

Wang, X.,Allen, S.,Blake, J.F.,Bowcut, V.,Briere, D.M.,Calinisan, A.,Dahlke, J.R.,Fell, J.B.,Fischer, J.P.,Gunn, R.J.,Hallin, J.,Laguer, J.,Lawson, J.D.,Medwid, J.,Newhouse, B.,Nguyen, P.,O'Leary, J.M.,Olson, P.,Pajk, S.,Rahbaek, L.,Rodriguez, M.,Smith, C.R.,Tang, T.P.,Thomas, N.C.,Vanderpool, D.,Vigers, G.P.,Christensen, J.G.,Marx, M.A.
Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor.
J.Med.Chem., 65:3123-3133, 2022

PubMed Abstract: KRAS, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRAS, selective inhibition of KRAS presents a significant challenge due to the requirement of inhibitors to bind KRAS with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRAS inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRAS mutant xenograft mouse tumor model.

PubMed: 34889605
DOI: 10.1021/acs.jmedchem.1c01688

Experimental method

X-RAY DIFFRACTION (1.29 Å)