European Journal of Medicinal Chemistry p. 765 - 781 (2014)
Update date:2022-08-17
Topics:
Chen, Danqi
Shen, Aijun
Li, Jian
Shi, Feng
Chen, Wuyan
Ren, Jing
Liu, Hongchun
Xu, Yechun
Wang, Xin
Yang, Xinying
Sun, Yiming
Yang, Min
He, Jianhua
Wang, Yueqin
Zhang, Liping
Huang, Min
Geng, Meiyu
Xiong, Bing
Shen, Jingkang
HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 Combining double low line 0.030 μM) and inhibited the proliferation of various human cancer cell lines with averaging GI50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C Combining double low line 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study.
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