Abstract 1570: Novel Myc-dependent compound DL78 selectively induces mitotic catastrophe and cell death in high grade serous ovarian cancer

Abstract While the rates of new cases and deaths for high grade serous ovarian cancer (HGSC) have declined steadily in the past decade, HGSC remains the fifth leading cause of cancer death in women. As many patients succumb to chemoresistance, there is a need to uncover novel targeted drugs. One way to do so is by drug repurposing. A computational screen, DrugPredict, led to the discovery that amiodarone, an antiarrhythmic, is a potent apoptosis-inducer and Myc-degrader in numerous patient-derived ovarian cancer cell lines. In search of a more selective, but less toxic compound, structure-activity relationship was applied to identify DL78. Due to its structural differences, DL78 is considered to be independent of amiodarone. DL78 lacks hERG activity, retains Myc regulation, and gains selective anticancer properties. This compound produces significant cell death selectively in patient-derived HGSC cells, including isogenic cisplatin-resistant lines, but does not harm non-transformed fallopian tube cells. Cancer cells treated with DL78 arrest prior to anaphase and showcase microtubule abnormalities and upregulation of mitotic regulators. The prolonged arrest leads to loss of Myc, mitotic catastrophe, and apoptosis selectively in the HGSC cells, while fallopian tube cells can cycle normally. DL78’s activity is confirmed to be dependent on Myc expression because targeted inhibition of Myc decreases its potency and prevents the DL78-induced cell cycle arrest. Finally, pharmacokinetic analysis shows that DL78 saturates the tumor following intraperitoneal injection, yet drug concentrations in the blood and liver present at normal levels. Overall, these phenotypes do not show with amiodarone treatment, suggesting that structurally different DL78 performs through a different mechanism. Further classification of this tumor-selective compound may reveal targeted ovarian cancer vulnerabilities. Citation Format: Jessica Teitel, Michele Cusato, Margaret Farah, Agharnan Gandhi, Pil Lee, Andrew White, John Takyi-Williams, Bo Wen, Andre Monterio Da Rocha, Analisa DiFeo. Novel Myc-dependent compound DL78 selectively induces mitotic catastrophe and cell death in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1570.