8UN5

KRAS-G13D-GDP in complex with Cpd38 ((E)-1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-3-(1,2,3,4-tetrahydroisoquinolin-8-yl)prop-2-en-1-one)

Summary for 8UN5

• Entry DOI: 10.2210/pdb8un5/pdb
• Descriptor: GTPase KRas, GLYCEROL, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: gtpase, kras, g13d, oncogenic, ribosome, hydrolase, oncoprotein-inhibitor complex, oncoprotein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 41128.86

Authors

Ultsch, M.H. (deposition date: 2023-10-18, release date: 2023-12-20, Last modification date: 2024-01-31)

Primary citation

Nilewski, C.,Labadie, S.,Wei, B.,Malhotra, S.,Do, S.,Gazzard, L.,Liu, L.,Shao, C.,Murray, J.,Izrayelit, Y.,Gustafson, A.,Endres, N.F.,Ma, F.,Ye, X.,Zou, J.,Evangelista, M.
Structure-Based Design and Evaluation of Reversible KRAS G13D Inhibitors.
Acs Med.Chem.Lett., 15:21-28, 2024

PubMed Abstract: Oncogenic mutations were identified decades ago, yet the selective inhibition of specific KRAS mutant proteins represents an ongoing challenge. Recent progress has been made in targeting certain P-loop mutant proteins, in particular KRAS G12C, for which the covalent inhibition of the GDP state via the Switch II pocket is now a clinically validated strategy. Inhibition of other KRAS mutant proteins such as KRAS G13D, on the other hand, still requires clinical validation. The remoteness of the D13 residue relative to the Switch II pocket in combination with the solvent exposure and conformational flexibility of the D13 side chain, as well as the difficulties of targeting carboxylate residues covalently, renders this specific protein particularly challenging to target selectively. In this report, we describe the design and evaluation of potent and KRAS G13D-selective reversible inhibitors. Subnanomolar binding to the GDP state Switch II pocket and biochemical selectivity over WT KRAS are achieved by leveraging a salt bridge with D13.

PubMed: 38229748
DOI: 10.1021/acsmedchemlett.3c00478

Experimental method

X-RAY DIFFRACTION (1.31 Å)