Li Xiaokai, Colvin Teresa, Rauch Jennifer N, Acosta-Alvear Diego, Kampmann Martin, Dunyak Bryan, Hann Byron, Aftab Blake T, Murnane Megan, Cho Min, Walter Peter, Weissman Jonathan S, Sherman Michael Y, Gestwicki Jason E
Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
Mol Cancer Ther. 2015 Mar;14(3):642-8. doi: 10.1158/1535-7163.MCT-14-0650. Epub 2015 Jan 6.
Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through multiple pathways, including FoxM1. Therefore, inhibitors of the Hsp70-Bag3 protein-protein interaction (PPI) may provide a noncanonical way to target this chaperone. We report that JG-98, an allosteric inhibitor of this PPI, indeed has antiproliferative activity (EC50 values between 0.3 and 4 μmol/L) across cancer cell lines from multiple origins. JG-98 destabilized FoxM1 and relieved suppression of downstream effectors, including p21 and p27. On the basis of these findings, JG-98 was evaluated in mice for pharmacokinetics, tolerability, and activity in two xenograft models. The results suggested that the Hsp70-Bag3 interaction may be a promising, new target for anticancer therapy.
热休克蛋白70（Hsp70）是一种应激诱导型分子伴侣，在癌症发展的多个步骤中发挥作用。事实证明，靶向Hsp70的活性位点颇具挑战性，这激发了人们对替代方法的兴趣。Hsp70与Bcl2相关抗凋亡蛋白3（Bag3）协同作用，通过包括叉头框蛋白M1（FoxM1）在内的多种途径促进细胞存活。因此，Hsp70-Bag3蛋白-蛋白相互作用（PPI）的抑制剂可能为靶向这种分子伴侣提供一种非传统方法。我们报告称，这种PPI的变构抑制剂JG-98确实对多种来源的癌细胞系具有抗增殖活性（半数有效浓度值在0.3至4 μmol/L之间）。JG-98使FoxM1不稳定，并解除了对包括p21和p27在内的下游效应分子的抑制。基于这些发现，在两种异种移植模型中对JG-98进行了小鼠药代动力学、耐受性和活性评估。结果表明，Hsp70-Bag3相互作用可能是一种有前景的新型抗癌治疗靶点。
