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<p>The Aurora-A kinase and its major regulator TPX2 act as key players during mitosis. Both are overexpressed in tumors, and the Aurora-A/TPX2 complex has been proposed as a potential oncogenic holoenzyme. Evidence of Aurora-A non-mitotic roles in cancer, some of which depend on its nuclear accumulation in interphase and are independent from the kinase activity, is emerging. Indeed, many Aurora-A ATP-competitive inhibitors have shown limited efficacy in clinical trials so far, highlighting the need for novel strategies to inhibit Aurora-A. Interestingly, our recent results suggest an involvement of TPX2 also in the non-mitotic protumorigenic roles of Aurora-A, which makes the Aurora-A/TPX2 complex a promising target. We previously described Aurora-A/TPX2 protein-protein interaction inhibitors. Here, starting from in silico analyses, we identified a new compound, i.e., ATC12, which we validated in vitro as a molecule able to bind Aurora-A and to compete with TPX2. We investigated the effects of ATC12 in 2D cultures and 3D mammospheres of breast cancer cell lines, as well as in patient-derived organoids, and observed an impairment of Aurora-A/TPX2 interaction and a decrease in cell viability and proliferation. Altogether, our observations support the targeting of the Aurora-A/TPX2 complex as a promising strategy for the development of novel anti-cancer therapeutics.</p>

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The ATC12 small molecule inhibits the Aurora-A/TPX2 interaction and impairs the proliferation of breast cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Dalila Boi,
  • Giulia Fianco,
  • Federica Polverino,
  • Francesco Fiorentino,
  • Anna Mastrangelo,
  • Simone Rossi,
  • Elisabetta Rubini,
  • Serena Rosignoli,
  • Francesca Troilo,
  • Maria Rosaria Antonelli,
  • Dalila Tarquini,
  • Laura Cervoni,
  • Serena Rinaldo,
  • Angela Tramonti,
  • Eleonora Kristina Scarpone,
  • Chiara Naro,
  • Claudio Sette,
  • Venturina Stagni,
  • Gianni Colotti,
  • Dante Rotili,
  • Alessandro Paiardini,
  • Giulia Guarguaglini,
  • Italia Anna Asteriti

摘要

The Aurora-A kinase and its major regulator TPX2 act as key players during mitosis. Both are overexpressed in tumors, and the Aurora-A/TPX2 complex has been proposed as a potential oncogenic holoenzyme. Evidence of Aurora-A non-mitotic roles in cancer, some of which depend on its nuclear accumulation in interphase and are independent from the kinase activity, is emerging. Indeed, many Aurora-A ATP-competitive inhibitors have shown limited efficacy in clinical trials so far, highlighting the need for novel strategies to inhibit Aurora-A. Interestingly, our recent results suggest an involvement of TPX2 also in the non-mitotic protumorigenic roles of Aurora-A, which makes the Aurora-A/TPX2 complex a promising target. We previously described Aurora-A/TPX2 protein-protein interaction inhibitors. Here, starting from in silico analyses, we identified a new compound, i.e., ATC12, which we validated in vitro as a molecule able to bind Aurora-A and to compete with TPX2. We investigated the effects of ATC12 in 2D cultures and 3D mammospheres of breast cancer cell lines, as well as in patient-derived organoids, and observed an impairment of Aurora-A/TPX2 interaction and a decrease in cell viability and proliferation. Altogether, our observations support the targeting of the Aurora-A/TPX2 complex as a promising strategy for the development of novel anti-cancer therapeutics.