8T4V

Crystal structure of compound 1 bound to K-Ras(G12D)

Summary for 8T4V

• Entry DOI: 10.2210/pdb8t4v/pdb
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, covalent, gtpase, oncoprotein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 45248.60

Authors

Zhang, Z.,Zheng, Q.,Guiley, K.Z.,Shokat, K.M. (deposition date: 2023-06-10, release date: 2024-03-13, Last modification date: 2024-10-16)

Primary citation

Zheng, Q.,Zhang, Z.,Guiley, K.Z.,Shokat, K.M.
Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D.
Nat.Chem.Biol., 20:1114-1122, 2024

PubMed Abstract: K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine in K-Ras-G12C mutation and lock it in a signaling-incompetent state. However, covalent inhibition of G12D, the most frequent K-Ras mutation particularly prevalent in pancreatic ductal adenocarcinoma, has remained elusive due to the lack of aspartate-targeting chemistry. Here we present a set of malolactone-based electrophiles that exploit ring strain to crosslink K-Ras-G12D at the mutant aspartate to form stable covalent complexes. Structural insights from X-ray crystallography and exploitation of the stereoelectronic requirements for attack of the electrophile allowed development of a substituted malolactone that resisted attack by aqueous buffer but rapidly crosslinked with the aspartate-12 of K-Ras in both GDP and GTP state. The GTP-state targeting allowed effective suppression of downstream signaling, and selective inhibition of K-Ras-G12D-driven cancer cell proliferation in vitro and xenograft growth in mice.

PubMed: 38443470
DOI: 10.1038/s41589-024-01565-w

Experimental method

X-RAY DIFFRACTION (1.47 Å)