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探索吡咯基二酮酸衍生物作为末端脱氧核苷酸转移酶非核苷抑制剂的构效关系。

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

作者信息

Madia Valentina Noemi, Garibaldi Nadia, Ialongo Davide, Patacchini Elisa, Tudino Valeria, Ruggieri Giuseppe, Zarbo Laura, Cara Emanuele, Coluccia Antonio, Artico Marco, Scipione Luigi, Messore Antonella, Saccoliti Francesco, Mentegari Elisa, Maga Giovanni, Di Santo Roberto, Crespan Emmanuele, Costi Roberta

机构信息

Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, Rome, Italy.

Institute of Molecular Genetics IGM-CNR, Pavia, Italy.

出版信息

J Enzyme Inhib Med Chem. 2025 Dec;40(1):2496782. doi: 10.1080/14756366.2025.2496782. Epub 2025 Jun 9.

DOI:10.1080/14756366.2025.2496782
PMID:40488680
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12150604/
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.

摘要

末端脱氧核苷酸转移酶（TdT）在某些癌症类型中过表达，它通过非经典的非同源末端连接途径驱动双链断裂的诱变修复。TdT酶与DNA聚合酶λ（pol λ）和β（pol β）同属于X家族聚合酶。然而，TdT仅表现出不依赖模板的核苷酸聚合作用。为了继续我们在开发TdT抑制剂方面的研究，在此我们深入研究了我们之前鉴定出的活性命中化合物的新结构类似物的构效关系。这里分析的二酮己烯酸衍生物对TdT表现出高选择性，抑制效力范围从低微摩尔到纳摩尔。对接研究突出了TdT结合中涉及的化学特征，这有助于合理说明酶抑制所需的结构要求。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/543d50d247ac/IENZ_A_2496782_F0007_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/36f8a7bac836/IENZ_A_2496782_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/66d712011f9f/IENZ_A_2496782_SCH0003_B.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/9df8e7b281c3/IENZ_A_2496782_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/543d50d247ac/IENZ_A_2496782_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/1a2f9ea5c1a1/IENZ_A_2496782_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/020c9e2f774b/IENZ_A_2496782_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/b6048576e6f0/IENZ_A_2496782_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/8ccc4f147c1d/IENZ_A_2496782_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/80fd5a48a320/IENZ_A_2496782_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/77a9e85969fd/IENZ_A_2496782_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/36f8a7bac836/IENZ_A_2496782_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/66d712011f9f/IENZ_A_2496782_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/a2155f86e0b2/IENZ_A_2496782_SCH0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/9e85b98199a1/IENZ_A_2496782_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/9df8e7b281c3/IENZ_A_2496782_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/726c/12150604/543d50d247ac/IENZ_A_2496782_F0007_C.jpg

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