Synthesis and Functional Proteomics Evaluation of Quinazolin-4-One Derivatives as Proteasome Inhibitors_Proteomics data_Part 2

Abstract: Quinazolinones have been recently recognized as preferred scaffolds for developing novel therapeutic opportunities: they indeed exhibit a wide range of biological activities, including antifungal, antitubercular, antihypertensive, anticancer, and antiviral ones. In this work, a focused library of new bioactive 4-(3-H)-quinazolinones has been synthesized, their cytotoxic action against DU-145 prostate cancer cells has been detailed and compound 4k has been revealed as the most active one. Consequently, its interactome has been characterized, using a label-free functional proteomics-based platform coupling Drug Affinity Responsive Target Stability (DARTS) and targeted Limited Proteolysis-Multiple Reaction Monitoring-Mass Spectrometry (t-LiP-MRM-MS). This multi-faced strategy has been employed to reveal few subunits of the 26S proteasome machinery as the most reliable compound 4k biological targets. This paved the way for the deepening of the protein–ligand interaction using in-vitro and in-silico bio-orthogonal techniques. Finally, the analysis of its function in living DU-145 cells prompted compound 4k as a new leading inhibitor of the chymotrypsin-like activity of the proteasomal β-5 subunit, stirring the quinazolinone framework for the development of new anticancer drugs.
This data set contains the following DARTS proteomics data: exp1, part 2

摘要：喹唑啉酮(Quinazolinones)近年来被认定为开发新型治疗方案的优先骨架母核，其具备抗真菌、抗结核、抗高血压、抗肿瘤及抗病毒等多种生物学活性。本研究合成了一系列具有生物活性的新型4-(3-H)-喹唑啉酮(4-(3-H)-Quinazolinones)聚焦文库，详细阐明了其对DU-145前列腺癌细胞的细胞毒作用，并确定化合物4k为其中活性最强的组分。
据此，本研究采用耦合了药物亲和响应靶点稳定性(Drug Affinity Responsive Target Stability, DARTS)与靶向有限蛋白水解-多反应监测-质谱(Targeted Limited Proteolysis-Multiple Reaction Monitoring-Mass Spectrometry, t-LiP-MRM-MS)的无标记功能蛋白质组学平台，对化合物4k的相互作用组进行了表征。该多维度策略成功鉴定出26S蛋白酶体复合物的数个亚基，为化合物4k最可靠的生物学靶点。这为通过体外(in-vitro)与虚拟(in-silico)生物正交技术深入探究蛋白质-配体相互作用奠定了基础。最后，通过对活DU-145细胞中化合物4k功能的分析，确定其为一种新型强效的蛋白酶体β-5亚基糜蛋白酶样活性抑制剂，为基于喹唑啉酮母核开发新型抗肿瘤药物开辟了新路径。
本数据集包含以下DARTS蛋白质组学数据：实验1（第二部分）