Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents

  • J Med Chem. 2024 Sep 12;67(17):15521-15536. doi: 10.1021/acs.jmedchem.4c01165.
Simon R Stockwell  1 ,  Duncan E Scott  2 ,  Gerhard Fischer  3 ,  Estrella Guarino  1 ,  Timothy P C Rooney  2 ,  Tzu-Shean Feng  2 ,  Tommaso Moschetti  3 ,  Rajavel Srinivasan  2 ,  Esther Alza  2 ,  Alice Asteian  2 ,  Claudio Dagostin  2 ,  Anna Alcaide  2 ,  Mathieu Rocaboy  3 ,  Beata Blaszczyk  3 ,  Alicia Higueruelo  3 ,  Xuelu Wang  3 ,  Maxim Rossmann  3 ,  Trevor R Perrior ,  Tom L Blundell  3 ,  David R Spring  2 ,  Grahame McKenzie  1 ,  Chris Abell  2 ,  John Skidmore  2 ,  Ashok R Venkitaraman  1 ,  Marko Hyvönen  3
Affiliations
  • 1. Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, U.K.
  • 2. Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • 3. Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
PMID: 39190548 DOI: 10.1021/acs.jmedchem.4c01165
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, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 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.

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