Pan-cancer Myc modulator that targets Myc-α-tubulin interaction to drive selective mitotic catastrophe

Abstract

Abstract MYC overexpression is a well-established cancer vulnerability, yet direct therapeutic targeting of Myc remains a challenge. Here, we identify DL78 as a potent antimitotic agent with selective anticancer activity through its regulation of Myc. DL78 demonstrated broad efficacy by inhibiting growth across nine cancer types and significantly reducing tumor burden in an in vivo model of platinum-resistant high-grade serous ovarian cancer, with no overt toxicity. DL78 preferentially targets chromosomally unstable, MYC -overexpressing cancer cells, a hallmark of high-grade serous ovarian cancer. Mechanistically, DL78 exploits Myc’s role in mitotic entry by disrupting its interaction with α-tubulin, leading to sustained mitotic arrest, mitotic catastrophe, and apoptosis while sparing nonmalignant cells. This study establishes a novel paradigm for Myc-targeted therapy by introducing DL78, which induces cancer-selective mitotic catastrophe by disrupting Myc’s interaction with α-tubulin rather than its transcriptional activity.