由于透明细胞肾细胞癌 (ccRCC) 分子多样性高、对标准治疗的反应率普遍较低以及普遍存在耐药性，传统化疗在治疗透明细胞肾细胞癌 (ccRCC) 方面的疗效往往受到限制。对 ccRCC 分子认识的最新进展，以及针对特定蛋白质的新型治疗药物的发现，显着改变了 ccRCC 的治疗前景。在这里，我们合成了 27 种新化合物，它们是 TG-101209 的衍生物，用于调节 BUB1B（BUB1 有丝分裂检查点丝氨酸/苏氨酸激酶 B）。基于 ccRCC 肿瘤的全局转录组学分析和基因共表达网络分析，BUB1B 最近被确定为开发有效 ccRCC 治疗的药物靶点。我们通过 1H 和 13C NMR 以及质谱法表征了这 27 种化合物的分子结构。我们通过分析 BUB1B 表达的调节来评估这 27 种化合物的效果。我们的主要目标是设计和评估这些新化合物在降低 ccRCC 细胞系 Caki-1 细胞活力方面的功效。我们通过 Schrödinger Maestro 软件进行了计算对接研究，并根据构效关系证明其中三种化合物（13a、5i 和 5j）有效下调 BUB1B 表达，并最终引发 Caki-1 细胞系的坏死和凋亡（SAR）分析。化合物 13a、5i 和 5j 的 IC50 值分别计算为 2.047 µM、10.046 µM 和 6.985 µM，表明它们对细胞活力具有有效的抑制作用。我们的研究表明，与传统使用的酪氨酸激酶抑制剂相比，这些靶向 BUB1B 的化合物可以为 ccRCC 治疗提供更有效、更有前景的方法。我们的研究强调了针对 ccRCC 特定分子途径的靶向治疗的潜力，可能为开发针对 ccRCC 的有效治疗策略开辟新途径。Crown 版权所有 © 2024。由 Elsevier Inc. 出版。保留所有权利。

The efficacy of conventional chemotherapies in treating clear cell renal cell carcinoma (ccRCC) is often limited due to its high molecular diversity, generally low response rates to standard treatments, and prevalent drug resistance. Recent advancements in the molecular understanding of ccRCC, alongside the discovery of novel therapeutic agents targeting specific proteins, have significantly altered the treatment landscape for ccRCC. Here, we synthesized 27 new compounds that are derivatives of TG-101209 to modulate BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B). BUB1B has been recently identified as a drug target for the development of effective ccRCC treatment based on global transcriptomics profiling of ccRCC tumours and gene co-expression network analysis. We characterized the molecular structures of these 27 compounds by 1H and 13C NMR and Mass spectrometry. We evaluated the effect of these 27 compounds by analysing the modulation of the BUB1B expression. Our primary objective was to design and assess the efficacy of these new compounds in reducing the viability of Caki-1 cells, a ccRCC cell line. We performed the computational docking studies by the Schrödinger Maestro software and demonstrated that three of these compounds (13a, 5i, and 5j) effectively downregulated BUB1B expression and eventually triggered necrosis and apoptosis in the Caki-1 cell line based on the structure-activity relationship (SAR) analysis. The IC50 values for compounds 13a, 5i, and 5j were calculated as 2.047 µM, 10.046 µM, and 6.985 µM, respectively, indicating their potent inhibitory effects on cell viability. Our study suggests that these compounds targeting BUB1B could offer a more effective and promising approach for ccRCC treatment compared to the conventionally used tyrosine kinase inhibitors. Our study underscores the potential of leveraging targeted therapies against specific molecular pathways in ccRCC may open new avenues for the development of effective treatment strategies against ccRCC.Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.