Introduction: Ovarian cancer, predominantly epithelial ovarian cancer (EOC), ranks as the most lethal gynecological cancer and the 5th leading cause of malignancy-related deaths in North American women. High-grade serous carcinoma (HGSC) is the most common EOC histological subtype. HGSCs show high intra-tumoral heterogeneity associated with widespread aneuploidy. Aneuploid cells appear to depend on small GTPase Ran for their survival and overexpression of Ran is observed in HGSC. Ran regulates homologous recombination and nonhomologous end joining DNA repair pathways by suppressing the nuclear receptor NR1D1. Ran knockdown inhibits the growth of EOC cells with limited effect on normal diploid cell proliferation. Methods and Results: We have generated and characterized small molecule compounds with the potential to inhibit Ran. We are prioritizing these compounds to test both efficacy and mode of action. We have identified highly promising Ran compounds that specifically inhibit proliferation and induce apoptosis of aneuploid cells but not that of diploid normal cells. We assessed the impact of these compounds on the downstream signaling of Ran by using NR1D1 as a biomarker. Active compounds modulated the stability of NR1D1 mRNA in EOC cells as measured by Q-PCR. No change in NR1D1 mRNA expression was found with non-active compounds or other anti-proliferative drugs such as Olaparib or Carboplatin. Moreover, direct specific binding of some of the inhibitors to the GTPase Ran has been analyzed by cellular thermal shift assay (CETSA). We are currently conducting mass spectrometry on cells treated with these compounds to elucidate how the interaction between Ran and its partner is affected. Conclusion and perspective: To date our results support targeting Ran as a successful strategy to treat HGSC. Future studies will focus on testing some of the most promising candidates in pre-clinical models.