A SMUG1 Inhibitor Modulates the Excision of Pyrimidine DNA Damage

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Abstract
Elevated activity of DNA repair enzymes that surveil pyrimidine damage has been associated with resistance to antitumor therapies. The DNA base excision repair (BER) enzyme SMUG1 recognizes and excises a number of modified and damaged pyrimidines that arise in cellular DNA, including deoxyuridine and 5-hydroxymethyl-dU, as well as the cytotoxic antitumor pyrimidine 5-fluorodeoxyuridine (5-FdU). Here we report the discovery and development of the first SMUG1 inhibitor scaffolds, derived from a small molecule sphingosine kinase inhibitor identified as a hit in assays against the DNA repair enzyme. Partial structural optimization resulted in compound SU0617, which inhibits SMUG1 with IC50 = 1.5 ± 0.1 μM and has ablated kinase inhibitory activity. We expect that the new inhibitor can be useful as a tool in studies of the overlapping substrate preferences of base excision repair enzymes and in the study of the pathways involved in responses to therapeutic nucleoside drugs.
Funding Information
  • Foundation for the National Institutes of Health (CA217809)
  • Foundation for the National Institutes of Health (GM145357)

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