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

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.