Exploring structure–activity relationships of pyrrolyl diketo acid derivatives as non-nucleoside inhibitors of terminal deoxynucleotidyl transferase enzyme

Abstract Terminal deoxynucleotidyl transferase (TdT) is overexpressed in some cancer types, where it drives the mutagenic repair of double strand breaks through non canonical non-homologous end joining pathway. The TdT enzyme belongs to the X family of polymerases, together with the DNA polymerase λ (pol λ) and β (pol β). However, TdT exclusively displays template-independent nucleotide polymerisation. Pursuing our studies in developing TdT inhibitors, herein we deepened the structure-activity relationships of new structural analogues of our previously identified hit compounds. The diketo hexenoic acid derivatives here analysed showed high selectivity towards TdT and inhibition potencies spanning from the low micromolar range to the nanomolar. Docking studies highlighted the chemical features involved in the TdT binding, well contributing to the rationalisation of the structural requirements needed for the enzymatic inhibition. Graphical Abstract

• Publication year

  2025

• Venue

  Journal of Enzyme Inhibition and Medicinal Chemistry

• Publication date

  2025-06-09

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1080/14756366.2025.2496782PMID 40488680PMCID 12150604
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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