Lead compound profiling for small molecule inhibitors of the REV1-CT/RIR Translesion synthesis Protein-Protein interaction.

Autor: Zaino AM; Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA., Dash RC; Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA., James SJ; Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA., MacGilvary N; Molecular Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA., Crompton A; University of Vermont Cancer Center and Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA., McPherson KS; Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT 06030, USA., Stanzione M; Massachusetts General Hospital Cancer Center, 149 13th Street Charlestown, Boston, MA, 02129, USA., Korzhnev DM; Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT 06030, USA., Dyson NJ; Massachusetts General Hospital Cancer Center, 149 13th Street Charlestown, Boston, MA, 02129, USA., Chatterjee N; University of Vermont Cancer Center and Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA., Cantor SB; Molecular Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA., Hadden MK; Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA. Electronic address: kyle.hadden@uconn.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 May 15; Vol. 106, pp. 117755. Date of Electronic Publication: 2024 May 09.
DOI: 10.1016/j.bmc.2024.117755
Abstrakt: Translesion synthesis (TLS) is a cellular mechanism through which actively replicating cells recruit specialized, low-fidelity DNA polymerases to damaged DNA to allow for replication past these lesions. REV1 is one of these TLS DNA polymerases that functions primarily as a scaffolding protein to organize the TLS heteroprotein complex and ensure replication occurs in the presence of DNA lesions. The C-Terminal domain of REV1 (REV1-CT) forms many protein-protein interactions (PPIs) with other TLS polymerases, making it essential for TLS function and a promising drug target for anti-cancer drug development. We utilized several lead identification strategies to identify various small molecules capable of disrupting the PPI between REV1-CT and the REV1 Interacting Regions (RIR) present in several other TLS polymerases. These lead compounds were profiled in several in vitro potency and PK assays to identify two scaffolds (1 and 6) as the most promising for further development. Both 1 and 6 synergized with cisplatin in a REV1-dependent fashion and demonstrated promising in vivo PK and toxicity profiles.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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