2. Academic Validation
  3. Exploring structure-activity relationships of pyrrolyl diketo acid derivatives as non-nucleoside inhibitors of terminal deoxynucleotidyl transferase enzyme

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

  • J Enzyme Inhib Med Chem. 2025 Dec;40(1):2496782. doi: 10.1080/14756366.2025.2496782.
Valentina Noemi Madia 1,  Nadia Garibaldi 2,  Davide Ialongo 1,  Elisa Patacchini 1,  Valeria Tudino 3,  Giuseppe Ruggieri 1 4,  Laura Zarbo 1,  Emanuele Cara 1,  Antonio Coluccia 1,  Marco Artico 5,  Luigi Scipione 1,  Antonella Messore 6,  Francesco Saccoliti 6,  Elisa Mentegari 2,  Giovanni Maga 2,  Roberto Di Santo 1,  Emmanuele Crespan 2,  Roberta Costi 1
Affiliations

Affiliations

  • 1 Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, Rome, Italy.
  • 2 Institute of Molecular Genetics IGM-CNR, Pavia, Italy.
  • 3 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
  • 4 Dottorato di Interesse Nazionale in One Health approaches to infectious diseases and life science research, Dipartimento di Sanità Pubblica, Medicina Sperimentale e Forense, Università degli Studi di Pavia, Pavia, Italy.
  • 5 Department of Sense Organs, Faculty of Medicine and Odontology, "Sapienza" Università di Roma, Rome, Italy.
  • 6 Department of Life Science, Health, and Health Professions, Link Campus University, Rome, Italy.
PMID: 40488680 DOI: 10.1080/14756366.2025.2496782
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.

Keywords

DNA repair; drug discovery; medicinal chemistry; structure–activity relationships; terminal deoxynucleotidyl transferase.

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