From unearthing to an intriguing cancer-fighting target: the human BCL-2 promoter G-quadruplex and i-motif.

Abstract

Cancer is a global burden that calls for creative solutions. Among the several hallmarks of cancer, overexpression of the BCL-2 oncogene serves as a factor for cancer cell proliferation and progression. Targeting the transcription machinery of the BCL-2 oncogene is an effective approach against cancer since chemotherapy causes huge problems due to its catastrophic toxicity and accompanying side effects. Transcription of the BCL-2 gene is primarily controlled by the P1 promoter and its upstream region, which is G-rich and can fold into G-quadruplexes (G4 or GQ), and i-motif structures. G4 and i-motif are secondary structures of nucleic acids that provide a platform for binding proteins, small molecules, peptide nucleic acids, etc. Such secondary structures can be targeted and have been extensively studied in the past few years. Therefore, it is reasonable to carry out an in-depth investigation of the G4 and i-motif structures in the BCL-2 gene and its potential as a therapeutic target. Here, we will overview the discovery and structure of BCL-2 G4 and i-motif structure and the proteins that bind to P1 promoter. Lastly, we will discuss BCL-2 G4 and i-motif binding small molecules/ligands, and their anticancer activities and examine their potential for innovative cancer treatments. © 2025 Elsevier B.V., All rights reserved.