Discovery of a Meisoindigo-Derived PROTAC as the ATM Degrader: Revolutionizing Colorectal Cancer Therapy via Synthetic Lethality with ATR Inhibitors

Abstract

Meisoindigo (Mei) has long been recognized in chronic myeloid leukemia (CML) treatment. To elucidate its molecular target and mechanisms, we embarked on designing and synthesizing a series of Mei-derived PROTACs. Through this endeavor, VHL-type PROTAC <b>9b</b> was identified to be highly cytotoxic against SW620, SW480, and K562 cells. Employing DiaPASEF-based quantitative proteomic analysis, in combination with extensive validation assays, we unveiled that <b>9b</b> potently and selectively degraded ATM across SW620 and SW480 cells in a ubiquitin-proteasome-dependent manner. <b>9b</b>-induced selective ATM degradation prompted DNA damage response cascades, thereby leading to the cell cycle arrest and cell apoptosis. This pioneering discovery renders the advent of ATM degradation for <i>anti</i>-cancer therapy. Notably, <b>9b</b>-induced ATM degradation synergistically enhanced the efficacy of ATR inhibitor AZD6738 both <i>in vitro</i> and <i>in vivo</i>. This work establishes the synthetic lethality-inducing properties of ATR inhibitors in the ATM-deficient context, thereby providing new avenues to innovative therapies for colorectal cancer.