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发现具有强效抗增殖特性的 IGF1R 抑制剂的脲取代 4-苯基噻唑衍生物。

Discovery of Ureido-Substituted 4-Phenylthiazole Derivatives as IGF1R Inhibitors with Potent Antiproliferative Properties.

机构信息

College of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China.

The Key Laboratory of Molecular and Cellular Biology and Drug Development in Universities of Liaoning Province, Jinzhou Medical University, Jinzhou 121001, China.

出版信息

Molecules. 2024 Jun 4;29(11):2653. doi: 10.3390/molecules29112653.

DOI:10.3390/molecules29112653
PMID:38893528
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11173463/
Abstract

The existing kinase inhibitors for hepatocellular carcinoma (HCC) have conferred survival benefits but are hampered by adverse effects and drug resistance, necessitating the development of novel agents targeting distinct pathways. To discover potent new anti-HCC compounds, we leveraged scaffold hopping from Sorafenib and introduced morpholine/piperidine moieties to develop ureido-substituted 4-phenylthiazole analogs with optimized physicochemical properties and binding interactions. Notably, compound exhibited potent cytotoxicity against HepG2 cells (IC = 0.62 ± 0.34 μM), significantly exceeding Sorafenib (IC = 1.62 ± 0.27 μM). Mechanistic investigations revealed that compound potently inhibited HCC cell migration and colony formation, and it induced G2/M arrest and early-stage apoptosis. Kinase profiling revealed IGF1R as a key target, which compound potently inhibited (76.84% at 10 μM). Molecular modeling substantiated compound 's strong binding to IGF1R via multiple hydrogen bonds. Computational predictions indicate favorable drug-like properties for compound . These findings provide a promising drug candidate for the treatment of HCC patients.

摘要

现有的用于肝细胞癌 (HCC) 的激酶抑制剂虽然带来了生存获益，但却受到不良反应和耐药性的限制，因此需要开发针对不同途径的新型药物。为了发现有效的新型抗 HCC 化合物，我们从索拉非尼(Sorafenib)中进行了骨架跳跃，并引入了吗啉/哌啶部分，以开发具有优化的物理化学性质和结合相互作用的脲取代的 4-苯基噻唑类似物。值得注意的是，化合物 对 HepG2 细胞具有很强的细胞毒性 (IC = 0.62 ± 0.34 μM)，明显优于索拉非尼 (IC = 1.62 ± 0.27 μM)。机制研究表明，化合物 能够强烈抑制 HCC 细胞的迁移和集落形成，并诱导 G2/M 期阻滞和早期凋亡。激酶谱分析显示 IGF1R 是一个关键靶点，化合物 能够强烈抑制 IGF1R (在 10 μM 时抑制率为 76.84%)。分子建模证实了化合物 通过多个氢键与 IGF1R 的强结合。计算预测表明化合物 具有良好的类药性。这些发现为治疗 HCC 患者提供了一种有前途的候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/a23097f5f6ee/molecules-29-02653-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/ad2b6e181c89/molecules-29-02653-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/401d9450dcca/molecules-29-02653-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/d5e64088f77c/molecules-29-02653-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/0659b2b5de5b/molecules-29-02653-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/5d60dced1689/molecules-29-02653-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/d9814d5c59ef/molecules-29-02653-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/0eaee7b61ca6/molecules-29-02653-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/bbbe39c9b2f0/molecules-29-02653-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/26e80127d7f2/molecules-29-02653-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/a23097f5f6ee/molecules-29-02653-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/ad2b6e181c89/molecules-29-02653-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/401d9450dcca/molecules-29-02653-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/d5e64088f77c/molecules-29-02653-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/0659b2b5de5b/molecules-29-02653-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/5d60dced1689/molecules-29-02653-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/d9814d5c59ef/molecules-29-02653-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/0eaee7b61ca6/molecules-29-02653-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/bbbe39c9b2f0/molecules-29-02653-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/26e80127d7f2/molecules-29-02653-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fa/11173463/a23097f5f6ee/molecules-29-02653-g009.jpg

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本文引用的文献

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Evolving therapeutic landscape of advanced hepatocellular carcinoma.晚期肝细胞癌不断演变的治疗格局。
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含磺酰基硫脲基团的噻唑烷-2,4-二酮类化合物作为有效的血管内皮生长因子受体-2（VEGFR-2）抑制剂和过氧化物酶体增殖物激活受体γ（PPARγ）激动剂的设计、分子对接、合成、抗癌及抗高血糖活性评估
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