The alchemist
VIP
First posted by @Idrus
Here is the research paper:
Abstract:
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, we 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 cancer-selective vulnerability.
Study limitations:
"We demonstrated a unique mechanism by which AOH1996 binds to PCNA and stabilizes the interaction between PCNA and RPB1, thereby interfering with the resolution of transcription-replication conflicts. Given the multifunctionality of PCNA, this action mechanism is unlikely the only way by which AOH1996 exerts its anti-cancer activity. Further studies of this compound on other aspects of PCNA functions will be needed to fully define its action mechanism. This study reports the anti-cancer activity of AOH1996 in a broad range of cancer cells and several animal tumor models. We acknowledge that positive animal study results do not always translate into success in treating cancer patients. Future clinical studies are necessary to determine its efficacy for cancer treatment."
Here is the research paper:
Abstract:
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, we 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 cancer-selective vulnerability.
Study limitations:
"We demonstrated a unique mechanism by which AOH1996 binds to PCNA and stabilizes the interaction between PCNA and RPB1, thereby interfering with the resolution of transcription-replication conflicts. Given the multifunctionality of PCNA, this action mechanism is unlikely the only way by which AOH1996 exerts its anti-cancer activity. Further studies of this compound on other aspects of PCNA functions will be needed to fully define its action mechanism. This study reports the anti-cancer activity of AOH1996 in a broad range of cancer cells and several animal tumor models. We acknowledge that positive animal study results do not always translate into success in treating cancer patients. Future clinical studies are necessary to determine its efficacy for cancer treatment."
