Small molecule targeting of transcription-replication conflict for selective chemotherapy

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 d...

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Published inCell chemical biology Vol. 30; no. 10; pp. 1235 - 1247.e6
Main Authors Gu, Long, Li, Min, Li, Caroline M., Haratipour, Pouya, Lingeman, Robert, Jossart, Jennifer, Gutova, Margarita, Flores, Linda, Hyde, Caitlyn, Kenjić, Nikola, Li, Haiqing, Chung, Vincent, Li, Hongzhi, Lomenick, Brett, Von Hoff, Daniel D., Synold, Timothy W., Aboody, Karen S., Liu, Yilun, Horne, David, Hickey, Robert J., Perry, J. Jefferson P., Malkas, Linda H.
Format Journal Article
LanguageEnglish
Published United States Elsevier Ltd 19.10.2023
Subjects
DNA repair
DNA replication stress
PCNA
transcription-replication conflict
transcription-replication conflict
PCNA
DNA repair
DNA replication stress
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Summary: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. [Display omitted] •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 Gu et al. used crystallography-directed medicinal chemistry to identify a small molecule ligand of PCNA that interferes with the resolution of transcription-replication conflicts. This compound was found to be orally active and inhibited tumor growth in animals without causing any discernable toxicity even at 6 times its effective dose.
Bibliography:AUTHOR CONTRIBUTIONS
L.H.M., R.J.H., Y.L., V.C., D.V.H., K.S.A., J.J.P.P., and L.G. conceptualized the idea and supervised the project; L.G., M.L., R.L., J.J., and C.M.L. designed and performed most experiments; T.W.S. designed and supervised the pharmacokinetics studies; D.H and P.H. were responsible for the design and synthesis of the analog compounds; M.G., L.F., and C.H. performed the in vivo combination therapy study; J.J. primarily performed the crystallography studies with support from N.K.; H.L. performed the computer modeling analysis; B.L. performed the proteomic study; H.L. analyzed the proteomic data; L.G. and J.J.P.P. wrote the manuscript.
ISSN:2451-9456
2451-9448
2451-9456
DOI:10.1016/j.chembiol.2023.07.001