Small molecule targeting of transcription-replication conflict for selective chemotherapy

Long Gu; Min Li; Caroline M Li; Pouya Haratipour; Robert Lingeman; Jennifer Jossart; Margarita Gutova; Linda Flores; Caitlyn Hyde; Nikola Kenjić; Haiqing Li; Vincent Chung; Hongzhi Li; Brett Lomenick; Daniel D Von Hoff; Timothy W Synold; Karen S Aboody; Yilun Liu; David Horne; Robert J Hickey; J Jefferson P Perry; Linda H Malkas

doi:10.1016/j.chembiol.2023.07.001

Small molecule targeting of transcription-replication conflict for selective chemotherapy

Cell Chem Biol. 2023 Oct 19;30(10):1235-1247.e6. doi: 10.1016/j.chembiol.2023.07.001. Epub 2023 Aug 1.

Authors

Long Gu¹, Min Li², Caroline M Li³, Pouya Haratipour⁴, Robert Lingeman³, Jennifer Jossart³, Margarita Gutova⁵, Linda Flores⁵, Caitlyn Hyde⁵, Nikola Kenjić⁶, Haiqing Li⁷, Vincent Chung⁸, Hongzhi Li⁹, Brett Lomenick¹⁰, Daniel D Von Hoff¹¹, Timothy W Synold¹², Karen S Aboody⁵, Yilun Liu², David Horne⁴, Robert J Hickey⁴, J Jefferson P Perry³, Linda H Malkas³

Affiliations

¹ Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA. Electronic address: Lgu@coh.org.
² Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
³ Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁴ Department of Cancer Biology & Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁵ Department of Developmental & Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁶ Department of Biochemistry, University of California Riverside, Riverside, CA, USA.
⁷ Department of Genomics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁸ Department of Medical Oncology, City of Hope, Duarte, CA, USA.
⁹ Department of Bioinformatics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
¹⁰ Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA, USA.
¹¹ Clinical Translational Research Division, Translational Genomics Research Institute, 445N 5th Street, Phoenix, AZ 85004, USA.
¹² Department of Medical Oncology and Therapeutics Research, Beckman Research Institute of City of Hope, Duarte, CA, USA.

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.

Keywords: DNA repair; DNA replication stress; PCNA; transcription-replication conflict.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Chromatin*
DNA
DNA Replication
Humans
Neoplasms* / drug therapy
Proliferating Cell Nuclear Antigen / chemistry
Proliferating Cell Nuclear Antigen / genetics
Proliferating Cell Nuclear Antigen / metabolism
Protein Binding

Substances

Proliferating Cell Nuclear Antigen
Chromatin
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding