Morretta Elva, Ruggiero Dafne, Belvedere Raffaella, Petrella Antonello, Bruno Ines, Terracciano Stefania, Monti Maria Chiara
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy.
Bioorg Chem. 2023 Sep;138:106620. doi: 10.1016/j.bioorg.2023.106620. Epub 2023 May 20.
In recent years, thiadiazolopyrimidine derivatives have been acknowledged for their striking poly-pharmacological framework, thus representing an interesting scaffold for the development of new therapeutic candidates. This paper examines the synthesis and the interactome characterization of a novel bioactive thiadiazolopyrimidone (compound 1), endowed with cytotoxic activity on HeLa cancer cells. In detail, starting from a small set of synthesized thiadiazolopyrimidones, a multi-disciplinary strategy has been carried out on the most bioactive one to disclose its potential biological targets by functional proteomics, using a label-free mass spectrometry based platform coupling Drug Affinity Responsive Target Stability and targeted Limited Proteolysis-Multiple Reaction Monitoring. The identification of Annexin A6 (ANXA6) as compound 1 most reliable cellular partner paved the way to deepen the protein-ligand interaction through bio-orthogonal approaches and to prove compound 1 action on migration and invasion processes governed by ANXA6 modulation. The identification of compund 1 as the first ANXA6 protein modulator represents a relevant tool to further explore the biological role of ANXA6 in cancer, as well as to develop novel anticancer candidates.
近年来，噻二唑并嘧啶衍生物因其显著的多药理学框架而受到认可，因此是开发新型治疗候选药物的一个有趣骨架。本文研究了一种新型生物活性噻二唑并嘧啶酮（化合物1）的合成及其相互作用组特征，该化合物对人宫颈癌HeLa细胞具有细胞毒性活性。具体而言，从一小部分合成的噻二唑并嘧啶酮开始，对活性最高的一种进行了多学科研究，通过功能蛋白质组学，使用基于无标记质谱的平台（结合药物亲和反应靶标稳定性和靶向有限蛋白酶解-多反应监测）来揭示其潜在的生物学靶点。鉴定出膜联蛋白A6（ANXA6）是化合物1最可靠的细胞伴侣，这为通过生物正交方法深入研究蛋白质-配体相互作用以及证明化合物1对由ANXA6调节的迁移和侵袭过程的作用铺平了道路。鉴定出化合物1是首个ANXA6蛋白调节剂，这是进一步探索ANXA6在癌症中的生物学作用以及开发新型抗癌候选药物的一个相关工具。
