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Discovery of novel heat shock protein (Hsp90) inhibitors based on luminespib with potent antitumor activity.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-04-02 , DOI: 10.1016/j.bmcl.2020.127165 Juyoung Jung 1 , Jinsun Kwon 2 , Soojung Hong 3 , An-Na Moon 3 , Jinah Jeong 3 , Sungwook Kwon 3 , Jeong-Ah Kim 3 , Myoungjae Lee 3 , Hongsub Lee 3 , Jin Hee Lee 3 , Jeewoo Lee 4
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-04-02 , DOI: 10.1016/j.bmcl.2020.127165 Juyoung Jung 1 , Jinsun Kwon 2 , Soojung Hong 3 , An-Na Moon 3 , Jinah Jeong 3 , Sungwook Kwon 3 , Jeong-Ah Kim 3 , Myoungjae Lee 3 , Hongsub Lee 3 , Jin Hee Lee 3 , Jeewoo Lee 4
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A series of isosteric surrogates of the 4-phenyl group in luminespib were investigated as new scaffolds of the Hsp90 inhibitor for the discovery of novel antitumor agents. Among the synthesized surrogates of isoxazole and pyrazole, compounds 4a, 5e and 12b exhibited potent Hsp90 inhibition in ATPase activity and Her2 degradation assays and significant antitumor activity in A2780 and HCT116 cell lines. Animal studies indicated that compared to luminespib, their activities were superior in A2780 or NCI-H1975 tumor xenograft models. A molecular modeling study demonstrated that compound 4a could fit nicely into the N-terminal ATP binding pocket.
中文翻译：
发现基于具有强大抗肿瘤活性的鲁米斯皮的新型热休克蛋白（Hsp90）抑制剂。
作为新发现的Hsp90抑制剂的支架，研究了Luminespib中一系列4-苯基的等排代孕替代物，以发现新型抗肿瘤药。在合成的异恶唑和吡唑替代物中，化合物4a，5e和12b在ATPase活性和Her2降解分析中表现出对Hsp90的有效抑制作用，在A2780和HCT116细胞系中表现出显着的抗肿瘤活性。动物研究表明，与luminespib相比，它们的活性在A2780或NCI-H1975肿瘤异种移植模型中更为出色。分子建模研究表明，化合物4a可以很好地适合N末端ATP的结合口袋。
更新日期：2020-04-02
中文翻译：
发现基于具有强大抗肿瘤活性的鲁米斯皮的新型热休克蛋白（Hsp90）抑制剂。
作为新发现的Hsp90抑制剂的支架，研究了Luminespib中一系列4-苯基的等排代孕替代物，以发现新型抗肿瘤药。在合成的异恶唑和吡唑替代物中，化合物4a，5e和12b在ATPase活性和Her2降解分析中表现出对Hsp90的有效抑制作用，在A2780和HCT116细胞系中表现出显着的抗肿瘤活性。动物研究表明，与luminespib相比，它们的活性在A2780或NCI-H1975肿瘤异种移植模型中更为出色。分子建模研究表明，化合物4a可以很好地适合N末端ATP的结合口袋。
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