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发现新型 2,4-二氨基嘧啶衍生物，含有 4-(吗啉甲基)苯基和取代苯甲酰胺，作为潜在的 FAK 抑制剂和抗癌剂。

Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and -Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents.

机构信息

Department of Chemistry, Changzhi University, Changzhi 046011, China.

Department of Public Health and Preventive Medicine, Changzhi Medical College, Changzhi 046011, China.

出版信息

Molecules. 2021 Jul 9;26(14):4187. doi: 10.3390/molecules26144187.

DOI:10.3390/molecules26144187
PMID:34299462
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8304610/
Abstract

Focal adhesion kinase (FAK) is responsible for the development and progression of various malignancies. With the aim to explore novel FAK inhibitors as anticancer agents, a series of 2,4-dianilinopyrimidine derivatives - and - containing 4-(morpholinomethyl)phenyl and -substituted benzamides have been designed and synthesized. Among them, compound displayed potent anti-FAK activity (IC = 0.047 ± 0.006 μM) and selective antiproliferative effects against H1975 (IC = 0.044 ± 0.011 μM) and A431 cells (IC = 0.119 ± 0.036 μM). Furthermore, compound also induced apoptosis in a dose-dependent manner, arresting the cells in S/G2 phase and inhibiting the migration of H1975 cells, all of which were superior to those of TAE226. The docking analysis of compound was performed to elucidate its possible binding modes with FAK. These results established as our lead compound to be further investigated as a potential FAK inhibitor and anticancer agent.

摘要

黏着斑激酶（FAK）在多种恶性肿瘤的发生和发展中起作用。为了探索新型 FAK 抑制剂作为抗癌药物，设计并合成了一系列含有 4-（吗啉甲基）苯基和 4-取代苯甲酰胺的 2,4-二氨基嘧啶衍生物 - 和 -。其中，化合物 表现出很强的抗 FAK 活性（IC = 0.047 ± 0.006 μM）和对 H1975（IC = 0.044 ± 0.011 μM）和 A431 细胞（IC = 0.119 ± 0.036 μM）的选择性增殖抑制作用。此外，化合物 还能以剂量依赖的方式诱导细胞凋亡，将细胞阻滞在 S/G2 期，并抑制 H1975 细胞的迁移，所有这些都优于 TAE226。对化合物 的对接分析表明了其与 FAK 可能的结合模式。这些结果确立 为我们的先导化合物，以进一步研究作为潜在的 FAK 抑制剂和抗癌药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/400a4a5aceae/molecules-26-04187-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/7db49aa25e91/molecules-26-04187-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/36317fdd4f81/molecules-26-04187-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/eff45f764599/molecules-26-04187-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/615890101405/molecules-26-04187-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/ee0912d72a9f/molecules-26-04187-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/1a83ab4a627b/molecules-26-04187-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/9f7e3c216e02/molecules-26-04187-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/400a4a5aceae/molecules-26-04187-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/7db49aa25e91/molecules-26-04187-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/36317fdd4f81/molecules-26-04187-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/eff45f764599/molecules-26-04187-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/615890101405/molecules-26-04187-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/ee0912d72a9f/molecules-26-04187-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/1a83ab4a627b/molecules-26-04187-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/9f7e3c216e02/molecules-26-04187-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d746/8304610/400a4a5aceae/molecules-26-04187-g007.jpg

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