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 invol

SUBMITTER: Madia VN 

PROVIDER: S-EPMC12150604 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature