Exploring structure–activity relationships of pyrrolyl diketo acid derivatives as non-nucleoside inhibitors of terminal deoxynucleotidyl transferase enzyme
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.
Authors
- Emmanuele Crespan (ORCID: https://orcid.org/0000-0003-0597-6929)
- Giuseppe Ruggieri
- Antonella Messore (ORCID: https://orcid.org/0000-0003-0158-5816)
- Elisa Mentegari
- Marco Artico (ORCID: https://orcid.org/0000-0002-8786-7007)
- Davide Ialongo (ORCID: https://orcid.org/0000-0002-4672-2936)
- Luigi Scipione (ORCID: https://orcid.org/0000-0002-2006-7005)
- Valentina Noemi Madia (ORCID: https://orcid.org/0000-0002-5724-612X)
- Roberta Costi (ORCID: https://orcid.org/0000-0002-1314-9029)
- Roberto Di Santo (ORCID: https://orcid.org/0000-0002-4279-7666)
- Elisa Patacchini (ORCID: https://orcid.org/0000-0002-4531-3612)
- Nadia Garibaldi (ORCID: https://orcid.org/0000-0003-0353-537X)
- Antonio Coluccia (ORCID: https://orcid.org/0000-0002-7940-8206)
- Francesco Saccoliti (ORCID: https://orcid.org/0000-0002-2907-5503)
- Valeria Tudino (ORCID: https://orcid.org/0000-0001-9024-9835)
- Giovanni Maga (ORCID: https://orcid.org/0000-0001-8092-1552)
- Laura Zarbo
- Emanuele Cara (ORCID: https://orcid.org/0009-0008-7723-2201)
Institutions
- University of Siena (IT)
- University of Pavia (IT)
- Istituto di Genetica Molecolare (IT)
- Institute of Molecular Genetics (RU)
- Istituto Pasteur (IT)
- Link Campus University (IT)
- The Sense Innovation and Research Center (CH)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Published
- 2025-06-09
- DOI
- https://doi.org/10.1080/14756366.2025.2496782
- Primary Topic
- HIV/AIDS drug development and treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00