Discovery of Y502-2304, a potent c-Myc G-quadruplex stabilizer for the treatment of multiple myeloma

Abstract

c-Myc is a proto-oncogene that is frequently overexpressed in various cancers, including multiple myeloma (MM), and is associated with poor clinical outcomes. Due to the lack of well-defined small-molecule binding pockets, directly targeting c-Myc remains a formidable challenge. The G-quadruplex (G4) formed in the NHE III1 region of the c-Myc promoter provides an alternative strategy to suppress c-Myc transcription. Given the structural features of thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine that are consistent with G4 stabilizers, we sought to identify novel compounds based on this scaffold. A structural similarity-based virtual screen of the ChemDiv small-molecule library identified 23 of its derivatives, which were prioritized for further investigation. Among these, compound Y502–2304 demonstrated selective stabilization of the c-Myc G4 structure and potent antiproliferative activity in MM cells. Moreover, Y502–2304 dose-dependently downregulated c-Myc mRNA and protein expression while exerting minimal effects on other G4-containing oncogenes. Mechanistically, Y502–2304 induced apoptosis in MM cells, characterized by elevated γH2AX levels, increased reactive oxygen species (ROS) generation, and mitochondrial dysfunction. It also activated the p53 pathway and upregulated the downstream pro-apoptotic proteins Noxa and PUMA. Y502–2304 significantly inhibited tumor growth in a xenograft MM model without inducing notable toxicity in vivo. These findings underscore Y502–2304 as a selective c-Myc G4 stabilizer with strong therapeutic potential for MM.