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6-氨基-2,4,5-三甲基-3-吡啶醇和 2-氨基-4,6-二甲基-5-嘧啶醇衍生物作为选择性成纤维细胞生长因子受体 4 抑制剂的设计、合成、分子对接和抗肝癌疗效评价。

6-Amino-2,4,5-trimethylpyridin-3-ol and 2-amino-4,6-dimethylpyrimidin-5-ol derivatives as selective fibroblast growth factor receptor 4 inhibitors: design, synthesis, molecular docking, and anti-hepatocellular carcinoma efficacy evaluation.

机构信息

College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.

Innovo Therapeutics Inc, Daejeon, Republic of Korea.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):844-856. doi: 10.1080/14756366.2022.2048378.

DOI:10.1080/14756366.2022.2048378
PMID:35296193
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8933034/
Abstract

A novel series of aminotrimethylpyridinol and aminodimethylpyrimidinol derivatives were designed and synthesised for FGFR4 inhibitors. Structure-activity relationship on the FGFR4 inhibitory activity of the new compounds was clearly elucidated by an intensive molecular docking study. Anti-cancer activity of the compounds was evaluated using hepatocellular carcinoma (HCC) cell lines and a chick chorioallantoic membrane (CAM) tumour model. Compound showed FGFR4 inhibitory activity over FGFR1 - 3. Compared to the positive control BLU9931, compound exhibited at least 8 times higher FGFR4 selectivity. Strong anti-proliferative activity of compound was observed against Hep3B, an HCC cell line which was a much more sensitive cell line to BLU9931. anti-tumour activity of compound against Hep3B-xenografted CAM tumour model was almost similar to BLU9931. Overall, compound , a novel derivative of aminodimethylpyrimidinol, was a selective FGFR4 kinase inhibitor blocking HCC tumour growth.

摘要

我们设计并合成了一系列新型的氨基三甲基吡啶醇和氨基二甲基嘧啶醇衍生物，用作 FGFR4 抑制剂。通过深入的分子对接研究，明确阐明了这些新化合物对 FGFR4 抑制活性的构效关系。我们使用肝癌 (HCC) 细胞系和鸡胚尿囊膜 (CAM) 肿瘤模型评估了化合物的抗癌活性。化合物 对 FGFR1-3 具有 FGFR4 抑制活性。与阳性对照物 BLU9931 相比，化合物 对 FGFR4 的选择性至少高 8 倍。化合物 在 Hep3B 细胞系（对 BLU9931 更为敏感的细胞系）中显示出强烈的抗增殖活性。化合物 对 Hep3B-xenografted CAM 肿瘤模型的抗肿瘤活性几乎与 BLU9931 相似。总之，新型氨基二甲基嘧啶醇衍生物 是一种选择性 FGFR4 激酶抑制剂，可阻断 HCC 肿瘤生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/da5e98549638/IENZ_A_2048378_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/80f966b609a5/IENZ_A_2048378_UF0001_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/b04600312c36/IENZ_A_2048378_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/f77109aa474a/IENZ_A_2048378_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/4a7f75fce0b8/IENZ_A_2048378_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/d318a9b98dc4/IENZ_A_2048378_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/8337169c0dfb/IENZ_A_2048378_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/c0c8877006c3/IENZ_A_2048378_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/56a7e474061f/IENZ_A_2048378_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/da5e98549638/IENZ_A_2048378_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/80f966b609a5/IENZ_A_2048378_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/9d8c660dfc33/IENZ_A_2048378_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/897e5259c402/IENZ_A_2048378_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/b04600312c36/IENZ_A_2048378_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/f77109aa474a/IENZ_A_2048378_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/4a7f75fce0b8/IENZ_A_2048378_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/d318a9b98dc4/IENZ_A_2048378_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/8337169c0dfb/IENZ_A_2048378_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/c0c8877006c3/IENZ_A_2048378_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/56a7e474061f/IENZ_A_2048378_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26f3/8933034/da5e98549638/IENZ_A_2048378_F0007_C.jpg

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