Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90
Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90
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新型四氢吡啶并[4,3-d]嘧啶作为伴侣热休克蛋白 90 的有效抑制剂。
DOI：
10.1021/acs.jmedchem.6b00912
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发表时间：
2016-12-08
影响因子：
7.3
通讯作者：
Xu, Xiao-Li
中科院分区：
文献类型：
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作者：
Jiang, Fen;Wang, Hui-Jie;Xu, Xiao-Li
热休克蛋白90（Hsp 90）是肿瘤治疗的潜在靶点。一些抑制剂已在临床试验中显示出抗肿瘤作用，从而刺激了小分子Hsp 90抑制剂的发现。在这里，我们描述了一个命中化合物，四氢吡啶并[4，3-d]嘧啶为基础的热休克蛋白90抑制剂15，它对热休克蛋白90表现出抑制活性的结构优化研究。合成了一系列类似物，并对其构效关系和构效关系进行了分析。这些探索导致了化合物73的发现，其在HCT 116异种移植模型中表现出有效的体外活性、良好的物理化学性质、有利的ADME性质和有效的抗肿瘤作用。此外，73在大鼠视网膜损伤模型中没有表现出眼毒性，表明其是相对安全的Hsp 90抑制剂。作为一种有前途的抗肿瘤药物，73正在进行进一步的临床前评价。
Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.