This month, a study published in the Cell Chemical Biology described a smallmolecule inhibitor of proliferating cell nuclear antigen (PCNA) that selectively killscancer cells. This time we may really find a cancer cure.

Proliferating cell nuclear antigen (PCNA) is an evolutionarily conserved multifacetedprotein found in all eukaryotic cells, and it plays a critical role in DNA synthesisand in DNA repair.

DNA replication stress is a hallmark of cancer cells. It is used as a major anti-cancertherapeutic strategy by exploiting this cancer-associated feature, through introductionof further DNA damage resulting in catastrophic damage to the cancer cell.

Due to its central role in DNA replication and repair, PCNA is a potential target forthis anti-cancer strategy. Moreover, the identification of a distinct isoform of PCNAassociated with cancer cells has potentially opened a novel avenue for thedevelopment of new chemotherapeutics.

Targeting transcription replication conflicts, a major source of endogenous DNAdouble-stranded breaks and genomic instability could have important anticancertherapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNAreplication and repair processes. Through a rational drug design approach, the teamidentified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells.

AOH1996 enhances the interaction between PCNA and the largest subunit of RNApolymerase II, RPB1, and dissociates PCNA from actively transcribed chromatinregions, while inducing DNA double-stranded breaks in a transcription-dependent manner.Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1’s PCNA-bindingregion, confers resistance to AOH1996. Orally administrable and metabolically stable,AOH1996 suppresses tumor growth as a monotherapy or as a combination treatmentbut causes no discernable side effects. Inhibitors of transcription replication conflictresolution may provide a new and unique therapeutic avenue for exploiting thiscancer-selective vulnerability.