8TXH

Crystal structure of KRAS G12D in complex with GDP and compound 14

Summary for 8TXH

• Entry DOI: 10.2210/pdb8txh/pdb
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: molecule, gtpase, kras, inhibitor, oncoprotein, oncoprotein-inhibitor complex, oncoprotein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 41056.06

Authors

Chen, P.,Irimia, A.,Yang, Z. (deposition date: 2023-08-23, release date: 2023-11-08)

Primary citation

Cheng, H.,Li, P.,Chen, P.,Irimia, A.,Bae, J.H.,Brooun, A.,Fagan, P.,Lam, R.,Lin, B.,Zhang, J.,Zhan, X.,Wu, X.,Xie, N.,Chiang, G.,Shoemaker, R.,Vernier, J.M.
Structure-Based Design and Synthesis of Potent and Selective KRAS G12D Inhibitors.
Acs Med.Chem.Lett., 14:1351-1357, 2023

PubMed Abstract: KRAS G12D mutation has been found in approximately 45% of pancreatic ductal adenocarcinoma (PDAC) cases, making it an attractive therapeutic target. Through structure-based drug design, a series of potent and selective KRAS G12D inhibitors were designed. The lead compound, ERAS-5024, inhibited ERK1/2 phosphorylation and cell proliferation in three-dimensional Cell-Titer Glo assays in AsPC-1 PDAC cells with single-digit nanomolar potency and caused tumor regression in the in vivo efficacy studies. We describe here the details of the design and synthesis program that led to the discovery of ERAS-5024.

PubMed: 37849557
DOI: 10.1021/acsmedchemlett.3c00245

Experimental method

X-RAY DIFFRACTION (1.2 Å)