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Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2017-12-29 , DOI: 10.1016/j.bmc.2017.12.041
Jian Liu , Chengbo Qian , Yehua Zhu , Jianguo Cai , Yufang He , Jie Li , Tianlin Wang , Haohao Zhu , Zhi Li , Wei Li , Lihong Hu

Both histone deacetylase (HDAC) and fibroblast growth factor receptor (FGFR) are important targets for cancer therapy. Although combining dual HDAC pharmacophore with tyrosine kinase inhibitors (TKIs) had achieved a successful progress, dual HDAC/FGFR1 inhibitors haven’t been reported yet. Herein, we designed a series of hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids scaffold with scaffold hopping and molecular hybridization strategies. Among them, compound 7j showed the most potent inhibitory activity against HDAC6 with IC50 of 34 nM and exhibited the great inhibitory activities against a human breast cancer cell line MCF-7 with IC50 of 9 μM in vitro. Meanwhile, the compound also exhibited moderate FGFR1 inhibitory activities. This study provides new tool compounds for further exploration of dual HDAC/FGFR1 inhibition.



中文翻译:

设计,合成和评估带有吲唑支架的新型双重FGFR1和HDAC抑制剂

组蛋白脱乙酰基酶(HDAC)和成纤维细胞生长因子受体(FGFR)都是癌症治疗的重要靶标。尽管将双重HDAC药效基团与酪氨酸激酶抑制剂(TKIs)结合已取得了成功的进展,但尚未报道双重HDAC / FGFR1抑制剂。在这里,我们设计了一系列带有1 H-吲哚-3-胺和苯并异羟肟酸支架的杂种,并采用了支架跳跃和分子杂交策略。其中,化合物7j对HDAC6的抑制作用最强,IC 50为34 nM,对人乳腺癌细胞系MCF-7的抑制作用最强,IC 50为9μM 。同时,该化合物还表现出中等的FGFR1抑制活性。这项研究为进一步探索双重HDAC / FGFR1抑制作用提供了新的工具化合物。

更新日期:2017-12-29
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