基于噻唑的成纤维细胞生长因子受体-1抑制剂的合成与生物学评价
Synthesis and Biological Evaluation of Thiazole-based Fibroblast Growth Factor Receptor-1 Inhibitors.
作者信息
Khanfar Mohammad A, Salman Ibrahim M, Ameer Omar Z
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, Alfaisal University, Al Takhassusi Rd, Riyadh 11533, Saudi Arabia.
Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, P.O Box 13140, Amman 11942, Jordan.
出版信息
Anticancer Agents Med Chem. 2024;24(15):1159-1165. doi: 10.2174/1871520622666220905141248.
BACKGROUND
The Fibroblast Growth Factor Receptor-1 (FGFR-1) is a tyrosine kinase and a validated target for the treatment of different cancer types.
OBJECTIVE
Design and synthesis of novel thiazole-based analogues of anticancer agents.
METHODS
Series of 2-aryl-5-methylthiazole analogues linked to structurally variable basic heads were synthesized as novel anticancer agents. Developed compounds were tested for their cytotoxic activities against several cancer cell lines.
RESULTS
Many analogues exhibited strong antiproliferative activities against breast cancer cell lines, with higher potency towards the highly metastatic form (MDA-MB-231). Pharmacophoric profiling using an in-house pharmacophore database identified FGFR-1 as a molecular target of active analogues. Synthesized compounds were bioassayed for their FGFR-1 inhibitory activities and many hits exhibited IC50 values in the low micromolar to nanomolar range.
CONCLUSION
The 2-aryl-5-methylthiazole linked to a basic head is a novel chemical scaffold of ATP-competitive inhibitor of FGFR-1 with potential therapeutic activities against different types of cancer.
背景
成纤维细胞生长因子受体-1（FGFR-1）是一种酪氨酸激酶，是治疗不同类型癌症的有效靶点。
目的
设计并合成新型基于噻唑的抗癌剂类似物。
方法
合成了一系列与结构可变的碱性基团相连的2-芳基-5-甲基噻唑类似物作为新型抗癌剂。对所开发的化合物进行了针对几种癌细胞系的细胞毒性活性测试。
结果
许多类似物对乳腺癌细胞系表现出强烈的抗增殖活性，对高转移性形式（MDA-MB-231）具有更高的效力。使用内部药效团数据库进行的药效团分析确定FGFR-1为活性类似物的分子靶点。对合成的化合物进行了FGFR-1抑制活性的生物测定，许多活性化合物的IC50值在低微摩尔至纳摩尔范围内。
结论
与碱性基团相连的2-芳基-5-甲基噻唑是FGFR-1的ATP竞争性抑制剂的新型化学骨架，对不同类型的癌症具有潜在治疗活性。
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