Discovery of small-sized tris-aryl imidazoles as bifunctional ligands for c-Myc and KRAS G-quadruplexes

Tumor growth promotion is achieved by overlapping intrinsic pathways of c-Myc and KRAS, and dual-targeting therapies emerge as an encouraging approach for drug discovery. G-quadruplexes (G4s) exist in the promoter regions of c-Myc and KRAS genes, rendering the transcriptional repression. G4 ligands are widely investigated in recent years, but dual-targeting ligands are still in their early stages. Therefore, tris-aryl imidazole analogs were designed and synthesized, with their binding properties to c-Myc and KRAS G4s confirmed firstly. HZ-1 was proven to be the most promising binder with relative selectivity to parallel G4s than non-parallel G4s. Then, the antitumor efficacy of HZ-1 was verified in human breast Cancer MDA-MB-231 cells through NRF2-XCT-GPX4 pathway, resulting in the occurrence of Ferroptosis, Apoptosis and immunogenic cell death (ICD). Finally, HZ-1 exerted potent tumor growth inhibition in vivo in BALB/c mice, without significant adverse effects to the mice. CD8⁺ cytotoxic T lymphocytes and CD4⁺ helper T lymphocytes were promoted by HZ-1 both in spleens and tumors. To sum up, the interaction of HZ analogs with multiple G4s formulates a new concept for Anticancer strategies.

C-Myc; G-quadruplex; Imidazole; KRAS; Small-size.