Department of Pharmaceutical Chemistry , University of California at San Francisco , Sandler Center, 675 Nelson Rising Lane , San Francisco , California 94158 , United States.
Urologic Oncology Branch, Center for Cancer Research , National Cancer Institute , Bethesda , Maryland 20892 , United States.
J Med Chem. 2018 Jul 26;61(14):6163-6177. doi: 10.1021/acs.jmedchem.8b00583. Epub 2018 Jul 13.
Cancer cells rely on the chaperone heat shock protein 70 (Hsp70) for survival and proliferation. Recently, benzothiazole rhodacyanines have been shown to bind an allosteric site on Hsp70, interrupting its binding to nucleotide-exchange factors (NEFs) and promoting cell death in breast cancer cell lines. However, proof-of-concept molecules, such as JG-98, have relatively modest potency (EC ≈ 0.7-0.4 μM) and are rapidly metabolized in animals. Here, we explored this chemical series through structure- and property-based design of ∼300 analogs, showing that the most potent had >10-fold improved EC values (∼0.05 to 0.03 μM) against two breast cancer cells. Biomarkers and whole genome CRISPRi screens confirmed members of the Hsp70 family as cellular targets. On the basis of these results, JG-231 was found to reduce tumor burden in an MDA-MB-231 xenograft model (4 mg/kg, ip). Together, these studies support the hypothesis that Hsp70 may be a promising target for anticancer therapeutics.
癌细胞依赖伴侣热休克蛋白 70（Hsp70）进行存活和增殖。最近，苯并噻唑罗丹明已被证明可结合 Hsp70 的别构位点，中断其与核苷酸交换因子（NEF）的结合，并促进乳腺癌细胞系的细胞死亡。然而，概念验证分子，如 JG-98，其效力相对较低（EC≈0.7-0.4μM），并且在动物体内迅速代谢。在这里，我们通过对约 300 个类似物进行基于结构和性质的设计来探索这一化学系列，结果表明，最有效的化合物对两种乳腺癌细胞的 EC 值提高了 10 多倍（约 0.05 至 0.03μM）。生物标志物和全基因组 CRISPRi 筛选证实了 Hsp70 家族成员是细胞靶标。基于这些结果，发现 JG-231 可减少 MDA-MB-231 异种移植模型中的肿瘤负担（4mg/kg，ip）。综上所述，这些研究支持了 Hsp70 可能是一种有前途的抗癌治疗靶点的假说。
