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

  • Cell Death Dis. 2026 Mar 24;17(1):356. doi: 10.1038/s41419-026-08579-3.
Dalila Boi  #  1 ,  Giulia Fianco  #  1 ,  Federica Polverino  1 ,  Francesco Fiorentino  2 ,  Anna Mastrangelo  1 ,  Simone Rossi  2 ,  Elisabetta Rubini  2 ,  Serena Rosignoli  3 ,  Francesca Troilo  1 ,  Maria Rosaria Antonelli  1 ,  Dalila Tarquini  1 ,  Laura Cervoni  2 ,  Serena Rinaldo  2 ,  Angela Tramonti  1 ,  Eleonora Kristina Scarpone  4 ,  Chiara Naro  4  5 ,  Claudio Sette  4  5 ,  Venturina Stagni  1  6 ,  Gianni Colotti  1 ,  Dante Rotili  7  8 ,  Alessandro Paiardini  9 ,  Giulia Guarguaglini  10 ,  Italia Anna Asteriti  11
Affiliations
  • 1. Institute of Molecular Biology and Pathology, National Research Council of Italy, c/o Sapienza University of Rome, Rome, Italy.
  • 2. Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy.
  • 3. Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • 4. GSTeP-Organoids Research Core Facility, IRCCS Fondazione Policlinico A. Gemelli, Rome, Italy.
  • 5. Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Rome, Italy.
  • 6. Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Signal transduction Unit, Rome, Italy.
  • 7. Department of Science, Roma Tre University, Rome, Italy.
  • 8. Biostructures and Biosystems National Institute (INBB), Rome, Italy.
  • 9. Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy. [email protected].
  • 10. Institute of Molecular Biology and Pathology, National Research Council of Italy, c/o Sapienza University of Rome, Rome, Italy. [email protected].
  • 11. Institute of Molecular Biology and Pathology, National Research Council of Italy, c/o Sapienza University of Rome, Rome, Italy. [email protected].
  • # Contributed equally.
PMID: 41876446 DOI: 10.1038/s41419-026-08579-3
Abstract

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.

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