A synthetic lethal approach to drug targeting of G-quadruplexes based on CX-5461

Abstract

DNA G-quadruplex (G4) structures are enriched at human genome loci critical for cancer development, such as in oncogene promoters, telomeres, and rDNA. Medicinal chemistry approaches to developing drugs that target G4 structures date back to over 20 years ago. Small-molecule drugs were designed to target and stabilize G4 structures, thereby blocking replication and transcription, resulting in cancer cell death. CX-3543 (Quarfloxin) was the first G4-targeting drug to enter clinical trials in 2005; however, because of the lack of efficacy, it was withdrawn from Phase 2 clinical trials. Efficacy problems also occurred in the clinical trial of patients with advanced hematologic malignancies using CX-5461 (Pidnarulex), another G4-stabilizing drug. Only after the discovery of synthetic lethal (SL) interactions between Pidnarulex and the BRCA1/2-mediated homologous recombination (HR) pathway in 2017, promising clinical efficacy was achieved. In this case, Pidnarulex was used in a clinical trial to treat solid tumors deficient in BRCA2 and PALB2. The history of the development of Pidnarulex highlights the importance of SL in identifying cancer patients responsive to G4-targeting drugs. In order to identify additional cancer patients responsive to Pidnarulex, several genetic interaction screens have been performed with Pidnarulex and other G4-targeting drugs using human cancer cell lines or C. elegans. Screening results confirmed the synthetic lethal interaction between G4 stabilizers and HR genes and also uncovered other novel genetic interactions, including genes in other DNA damage repair pathways and genes in transcription, epigenetic, and RNA processing deficiencies. In addition to patient identification, synthetic lethality is also important for the design of drug combination therapy for G4-targeting drugs in order to achieve better clinical outcomes.