8C1G

Aurora A kinase in complex with TPX2-inhibitor 7

Summary for 8C1G

• Entry DOI: 10.2210/pdb8c1g/pdb
• Descriptor: Aurora kinase A, 4-(4-chlorophenyl)-~{N}-(dimethylsulfamoyl)-7-methyl-1~{H}-indole-6-carboxamide, ADENOSINE-5'-DIPHOSPHATE, ... (10 entities in total)
• Functional Keywords: protein-ligand complex, kinase, protein-protein interaction inhibitor, cell cycle
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32770.03

Authors

Fischer, G.,Rocaboy, M.,Blaszczyk, B.,Moschetti, T.,Wang, X.,Scott, D.E.,Coyne, A.G.,Dagostin, C.,Rooney, T.,Bayly, A.,Feng, J.,Asteian, A.,Alcaide-Lopez, A.,Stockwell, S.,Skidmore, J.,Venkitaraman, A.R.,Abell, C.,Blundell, T.L.,Hyvonen, M. (deposition date: 2022-12-20, release date: 2024-01-10, Last modification date: 2024-09-25)

Primary citation

Stockwell, S.R.,Scott, D.E.,Fischer, G.,Guarino, E.,Rooney, T.P.C.,Feng, T.S.,Moschetti, T.,Srinivasan, R.,Alza, E.,Asteian, A.,Dagostin, C.,Alcaide, A.,Rocaboy, M.,Blaszczyk, B.,Higueruelo, A.,Wang, X.,Rossmann, M.,Perrior, T.R.,Blundell, T.L.,Spring, D.R.,McKenzie, G.,Abell, C.,Skidmore, J.,Venkitaraman, A.R.,Hyvonen, M.
Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.
J.Med.Chem., 67:15521-15536, 2024

PubMed Abstract: Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, , inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.

PubMed: 39190548
DOI: 10.1021/acs.jmedchem.4c01165

Experimental method

X-RAY DIFFRACTION (1.96 Å)