New PCNA Inhibitor AOH1996
This month, a study published in the Cell Chemical Biology described a small
molecule inhibitor of proliferating cell nuclear antigen (PCNA) that selectively kills
cancer cells. This time we may really find a cancer cure.
Proliferating cell nuclear antigen (PCNA) is an evolutionarily conserved multifaceted
protein found in all eukaryotic cells, and it plays a critical role in DNA synthesis
and in DNA repair.
DNA replication stress is a hallmark of cancer cells. It is used as a major anti-cancer
therapeutic strategy by exploiting this cancer-associated feature, through introduction
of 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 for
this anti-cancer strategy. Moreover, the identification of a distinct isoform of PCNA
associated with cancer cells has potentially opened a novel avenue for the
development of new chemotherapeutics.
Targeting transcription replication conflicts, a major source of endogenous DNA
double-stranded breaks and genomic instability could have important anticancer
therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA
replication and repair processes. Through a rational drug design approach, the team
identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells.
AOH1996 enhances the interaction between PCNA and the largest subunit of RNA
polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin
regions, 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-binding
region, confers resistance to AOH1996. Orally administrable and metabolically stable,
AOH1996 suppresses tumor growth as a monotherapy or as a combination treatment
but causes no discernable side effects. Inhibitors of transcription replication conflict
resolution may provide a new and unique therapeutic avenue for exploiting this
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