9KDS

The crystal structure of human AURKA kinase domain in complex with RA1

This is a non-PDB format compatible entry.

Summary for 9KDS

• Entry DOI: 10.2210/pdb9kds/pdb
• Descriptor: Aurora kinase A (2 entities in total)
• Functional Keywords: inhibitor, cytokine
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 31387.36

Authors

Zhang, Z.M.,Wang, L. (deposition date: 2024-11-04, release date: 2025-10-22)

Primary citation

Chen, P.,Wang, L.,Wang, X.,Sun, J.,Miao, F.,Wang, Z.,Yang, F.,Xiang, M.,Gu, M.,Li, S.,Zhang, J.,Yuan, P.,Lu, X.,Zhang, Z.M.,Gao, L.,Yao, S.Q.
Cell-Active, Arginine-Targeting Irreversible Covalent Inhibitors for Non-Kinases and Kinases.
Angew.Chem.Int.Ed.Engl., 64:e202422372-e202422372, 2025

PubMed Abstract: Targeted covalent inhibitors (TCIs) play an essential role in the fields of kinase research and drug discovery. TCI strategies to target more common amino acid side-chains have yet to be demonstrated. Targeting other amino acids would also expand the pharmaceutical industry's toolbox for targeting other tough-to-drug proteins. We report herein a glyoxal-based, arginine-reactive strategy to generate potent and selective small-molecule TCIs of Mcl-1 (an important anti-apoptotic protein) by selectively targeting the conserved arginine (R263) in the protein. We further validated the generality of this strategy by developing glyoxal-based, irreversible covalent inhibitors of AURKA (a cancer-related kinase) that showed exclusive reactivity with a solvent-exposed arginine (R220) of this enzyme. We showed the resulting compounds were potent, selective and cell-active, capable of covalently engaging endogenous AURKA in MV-4-11 cells with long residence time. Finally, we showed the potential application of glyoxal-based TCIs in targeting an acquired drug-resistance mutant of ALK kinase (G1202R).

PubMed: 39778034
DOI: 10.1002/anie.202422372

Experimental method

X-RAY DIFFRACTION (2.50011813338 Å)