ABSTRACT: High grade serous cancer (HGSC) is the most common, and most lethal, form of ovarian cancer due to its molecular heterogeneity and lack of preventative screening. As patients succumb to chemoresistance, there is a need to uncover novel targeted drugs. Previously, utilizing a computational screen, DrugPredict, we discovered 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, which lacks hERG activity, retains Myc regulation, and gains selective anticancer properties. This compound produces significant growth inhibition across numerous cancer types, including HGSC patient derived cells, as well as isogenic cisplatin-resistant lines, but does not affect nonmalignant fallopian tube cells. Utilizing a fluorescent-based cell target engagement platform, we confirmed that DL78 directly interacts with Myc. DL78 leverages the amplification of Myc, which is seen in greater than 50% of HGSC tumors to force uncontrolled mitotic entry, mitotic catastrophe, and apoptosis specifically in HGSC cells, while fallopian tube cells have slowed growth and no change in Myc. DL78 also induces abnormal spindle polarity in cancer cells and disrupts the interaction between α-tubulin and Myc. We have shown that DL78’s activity is confirmed to be dependent on MYC expression and compounds with similar structure that do not degrade Myc lack biological activity. Finally, pharmacokinetic analysis shows that DL78 specifically infiltrates the tumor within 3 hours, however the compound maintains a low concentration and high clearance in the bloodstream of normal mice. Overall, DL78 is a novel Myc modulator with a unique mechanism of action disrupting Myc’s interaction with α-tubulin leading to mitotic catastrophe and loss of Myc.
