Abstract 4003: Identification of a targeted anti-mitotic agent that degrades Myc and specifically induces cancer cell death

Abstract

For decades, chemotherapy has remained the standard of care for ovarian cancer patients. Although 70% of patients initially respond to platinum-based therapy, >90% succumb to chemoresistance. There is a need to uncover targeted drugs for ovarian cancer. A quicker, more cost-effective, and lower-risk route to identify new treatments is through repurposing FDA approved drugs. Using a computational drug repositioning platform, DrugPredict, we previously uncovered that the antiarrhythmic drug amiodarone potently decreases cell viability and triggers apoptosis in numerous patient-derived ovarian cancer cell lines through the degradation of c-Myc. However, given the dose-limiting toxicity of amiodarone, we applied structure-activity relationship to identify DL78, which lacks hERG activity but retains the anti-cancer properties and ability to regulate Myc. DL78 is significantly more potent and tumor specific than amiodarone. It rapidly induces G2/M arrest which ultimately leads to loss of Myc, mitotic catastrophe, and apoptosis in several types of cancer cells. Furthermore, pharmacokinetics studies show that the compound is retained in the tumor upon intraperitoneal injection and has reasonable solubility and permeability, yielding good absorption, distinct from amiodarone. Given its structural and molecular differences, we expect that DL78 works through a different mechanism that amiodarone and could represent an effective treatment for ovarian cancer and other MYC-driven tumors. Additional studies will establish the foundation for further development of this novel compound, as well as reveal targeted ovarian cancer vulnerabilities. Citation Format: Jessica McAnulty, Michele Dziubinski, Agharnan Gandhi, Margaret Farah, Pil Lee, Andrew D. White, Analisa DiFeo. Identification of a targeted anti-mitotic agent that degrades Myc and specifically induces cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4003.