2. Academic Validation
  3. Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168022
    Aurora A-TPX2相互作用抑制剂
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