3H10

Aurora A inhibitor complex

Summary for 3H10

• Entry DOI: 10.2210/pdb3h10/pdb
• Related: 3COH 3H0Y 3H0Z
• Descriptor: Serine/threonine-protein kinase 6, 9-chloro-7-(2,6-difluorophenyl)-N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine (3 entities in total)
• Functional Keywords: protein:inhibitor complex aurora-a, cell cycle, serine/threonine, protein kinase, atp-binding, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton, centrosome: O14965
• Total number of polymer chains: 3
• Total formula weight: 94820.20

Authors

Wiesmann, C.,Ultsch, M.H.,Cochran, A.G. (deposition date: 2009-04-10, release date: 2009-07-07, Last modification date: 2024-02-21)

Primary citation

Aliagas-Martin, I.,Burdick, D.,Corson, L.,Dotson, J.,Drummond, J.,Fields, C.,Huang, O.W.,Hunsaker, T.,Kleinheinz, T.,Krueger, E.,Liang, J.,Moffat, J.,Phillips, G.,Pulk, R.,Rawson, T.E.,Ultsch, M.,Walker, L.,Wiesmann, C.,Zhang, B.,Zhu, B.Y.,Cochran, A.G.
A class of 2,4-bisanilinopyrimidine Aurora A inhibitors with unusually high selectivity against Aurora B.
J.Med.Chem., 52:3300-3307, 2009

PubMed Abstract: The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.

PubMed: 19402633
DOI: 10.1021/jm9000314

Experimental method

X-RAY DIFFRACTION (2.2 Å)