Validation of the Hsp70-Bag3 Protein-Protein Interaction as a Potential Therapeutic Target in Cancer,Molecular Cancer Therapeutics

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Validation of the Hsp70-Bag3 Protein-Protein Interaction as a Potential Therapeutic Target in Cancer
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2015-01-06 , DOI: 10.1158/1535-7163.mct-14-0650
Xiaokai Li ₁ , Teresa Colvin ₂ , Jennifer N. Rauch ₁ , Diego Acosta-Alvear ₃ , Martin Kampmann ₄ , Bryan Dunyak ₁ , Byron Hann ₅ , Blake T. Aftab ₅ , Megan Murnane ₅ , Min Cho ₄ , Peter Walter ₃ , Jonathan S. Weissman ₄ , Michael Y. Sherman ₂ , Jason E. Gestwicki ₁

Affiliation

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. Mol Cancer Ther; 14(3); 642–8. ©2015 AACR.

中文翻译：

Hsp70-Bag3 蛋白质-蛋白质相互作用作为癌症潜在治疗靶点的验证

Hsp70 是一种压力诱导型分子伴侣，在几个步骤中是癌症发展所必需的。已证明靶向 Hsp70 的活性位点相对具有挑战性，从而推动了对替代方法的兴趣。Hsp70 与 Bcl2 相关的 athanogene 3 (Bag3) 合作，通过包括 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) 的抑制剂可能提供一种非规范的方式来靶向这种分子伴侣。我们报告说，这种 PPI 的变构抑制剂 JG-98 确实对来自多个来源的癌细胞系具有抗增殖活性（EC50 值介于 0.3 和 4 μmol/L 之间）。JG-98 使 FoxM1 不稳定并解除对下游效应子的抑制，包括 p21 和 p27。基于这些发现，JG-98 在小鼠中进行了药代动力学评估，两种异种移植模型的耐受性和活性。结果表明 Hsp70-Bag3 相互作用可能是抗癌治疗的一个有前途的新靶点。摩尔癌症治疗; 14(3); 642-8。©2015 AACR。

更新日期：2015-01-06

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