Forsberg Leah K, Liu Weiya, Holzbeierlein Jeffrey, Blagg Brian S J
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, Kansas 66045-7563, United States.
Department of Urology, 3901 Rainbow Boulevard, Stop 3016, The University of Kansas Medical Center, Kansas City, Kansas 66160, United States.
Bioorg Med Chem Lett. 2017 Sep 15;27(18):4514-4519. doi: 10.1016/j.bmcl.2017.07.030. Epub 2017 Jul 11.
Heat Shock Protein 90 (Hsp90) is a molecular chaperone under clinical investigation for the treatment of neurodegenerative diseases and cancer. Neuroprotective Hsp90 C-terminal inhibitors (novologues) contain a biaryl ring system, and include KU-596, which was modified and investigated for potential anti-cancer activity. Incorporation of a benzamide group onto the biaryl novologues in lieu of the acetamide yielded compounds that manifest anti-cancer activity. Further exploration of the central phenyl ring led to compounds with enhanced anti-proliferative activity. The design, synthesis, and evaluation of these new analogs against breast and prostate cancer cell lines is reported herein, where it was found that 8b and 10 manifest potent anti-proliferative activity and a robust degradation of Hsp90 client-dependent proteins.
热休克蛋白90（Hsp90）是一种正在进行临床研究以治疗神经退行性疾病和癌症的分子伴侣。具有神经保护作用的Hsp90 C末端抑制剂（新型化合物）含有联芳基环系统，包括KU-596，该化合物经过修饰并研究了其潜在的抗癌活性。在联芳基新型化合物上引入苯甲酰胺基团以取代乙酰胺，得到了具有抗癌活性的化合物。对中心苯环的进一步探索产生了具有增强抗增殖活性的化合物。本文报道了这些新类似物针对乳腺癌和前列腺癌细胞系的设计、合成及评估，结果发现8b和10表现出强大的抗增殖活性以及对Hsp90客户依赖性蛋白的显著降解作用。
