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Small molecule targeting of transcription-replication conflict for selective chemotherapy
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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.
https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(23)00221-0#
- Long Gu
- Min Li
- Caroline M. Li
- Robert J. Hickey
- J. Jefferson P. Perry
- Linda H. Malkas [SUP]12[/SUP]
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Previous ArticleArabinose- and xylose-modified analogs of 2′,3′-cGAMP act …
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Crystallography-directed medicinal chemistry identifies a PCNA ligand (AOH1996) - •
AOH1996 enhances PCNA and RPB1 interaction and interferes with TRC resolution - •
AOH1996 induces DNA double-stranded breaks in a transcription dependent manner - •
Given orally, AOH1996 suppresses tumor growth but causes no discernable side effect
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.
https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(23)00221-0#