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

## TL;DR

This study explores how the structure of pyrrolyl diketo acid compounds affects their ability to inhibit the TdT enzyme, which is linked to cancer.

## Contribution

The paper presents new structural analogues with improved selectivity and potency as TdT inhibitors.

## Key findings

- Diketo hexenoic acid derivatives showed high selectivity and inhibition potency against TdT.
- Docking studies revealed key chemical features important for TdT binding and inhibition.
- The compounds' structure-activity relationships were rationalized for enzymatic inhibition.

## 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.