8WB1
Crystal Structure of small molecule KN2H covalently bound to K-Ras(G12D)
Summary for 8WB1
| Entry DOI | 10.2210/pdb8wb1/pdb |
| Descriptor | GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total) |
| Functional Keywords | covalent inhibitor, kras g12d, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20559.09 |
| Authors | Zhou, L.,Zhang, R.,Shuai, T.B. (deposition date: 2023-09-08, release date: 2024-09-11, Last modification date: 2026-09-30) |
| Primary citation | Shuai, T.,Zhang, R.,Yuan, Z.,Zhang, M.,Fan, Z.,Ruan, X.,Qi, Z.,Xie, W.,Liu, P.,Uesugi, M.,Li, Q.,Qu, Z.,Tan, M.,Su, H.,Zhou, L. Expanding the Chemistry of Acyl Diazo Electrophile as a Tunable Warhead for Covalent Targeting of KRAS (G12D) Mutant. J.Med.Chem., 68:21427-21440, 2025 Cited by PubMed Abstract: Covalent warheads are indispensable in the design and development of targeted covalent inhibitors (TCIs). Here, we designed and evaluated acyl diazo probes as an aspartic acid/glutamic acid targeted warhead. Among these probes, demonstrated chemoselectivity for carboxyl residues, even under complex physiological conditions, effectively modifying the proteome in both cell lysates and live cells. Subsequently, we incorporated the warhead onto MRTX-1133, a potent ligand of the KRAS (G12D) mutant, to generate a novel TCI called . Compared with other mutants, demonstrated covalent modification specifically targeting the KRAS (G12D) mutant, with notable chemoselectivity. It also possessed strong antiproliferative activity against KRAS (G12D) mutant cell lines by downregulating RAS oncogenic signaling. Our findings provide a novel strategy for designing novel TCIs targeting carboxyl residues, based on acyl diazo warheads. PubMed: 41017113DOI: 10.1021/acs.jmedchem.5c01365 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.72 Å) |
Structure validation
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