Your browser doesn't support javascript.
loading
Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.
Stockwell, Simon R; Scott, Duncan E; Fischer, Gerhard; Guarino, Estrella; Rooney, Timothy P C; Feng, Tzu-Shean; Moschetti, Tommaso; Srinivasan, Rajavel; Alza, Esther; Asteian, Alice; Dagostin, Claudio; Alcaide, Anna; Rocaboy, Mathieu; Blaszczyk, Beata; Higueruelo, Alicia; Wang, Xuelu; Rossmann, Maxim; Perrior, Trevor R; Blundell, Tom L; Spring, David R; McKenzie, Grahame; Abell, Chris; Skidmore, John; Venkitaraman, Ashok R; Hyvönen, Marko.
Afiliación
  • Stockwell SR; Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, U.K.
  • Scott DE; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Fischer G; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
  • Guarino E; Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, U.K.
  • Rooney TPC; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Feng TS; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Moschetti T; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
  • Srinivasan R; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Alza E; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Asteian A; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Dagostin C; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Alcaide A; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Rocaboy M; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
  • Blaszczyk B; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
  • Higueruelo A; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
  • Wang X; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
  • Rossmann M; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
  • Blundell TL; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
  • Spring DR; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • McKenzie G; Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, U.K.
  • Abell C; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Skidmore J; Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • Venkitaraman AR; Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, U.K.
  • Hyvönen M; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
J Med Chem ; 67(17): 15521-15536, 2024 Sep 12.
Article en En | MEDLINE | ID: mdl-39190548
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 ATPX2 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.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Ciclo Celular / Antimitóticos / Aurora Quinasa A / Proteínas Asociadas a Microtúbulos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Ciclo Celular / Antimitóticos / Aurora Quinasa A / Proteínas Asociadas a Microtúbulos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos