Small-molecule inhibitor targeting the Hsp70-Bim protein-protein interaction in CML cells overcomes BCR-ABL-independent TKI resistance
Small-molecule inhibitor targeting the Hsp70-Bim protein-protein interaction in CML cells overcomes BCR-ABL-independent TKI resistance
复制标题
靶向 CML 细胞中 Hsp70-Bim 蛋白-蛋白相互作用的小分子抑制剂克服了不依赖于 BCR-ABL 的 TKI 耐药性
DOI：
10.1038/s41375-021-01283-5
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发表时间：
2021-05-18
期刊：
影响因子：
11.4
通讯作者：
Zhang, Zhichao
中科院分区：
文献类型：
--
作者：
Song, Ting;Guo, Yafei;Zhang, Zhichao
在此，我们从 Bcl-2 抑制剂库中筛选出一种新型 Hsp70-Bim 蛋白-蛋白相互作用 (PPI) 抑制剂 S1g-2；该化合物通过直接结合与变构 Hsp70 抑制剂 MKT-077 相邻的未知位点特异性破坏 Hsp70-Bim PPI，在亚 mu M 浓度范围内显示出结合亲和力。与其他癌细胞、正常淋巴细胞和 BaF3 细胞相比，S1g-2 在 CML 细胞、原发性 CML 母细胞和 BCR-ABL 转化的 BaF3 细胞中表现出总体高 5-10 倍的凋亡诱导活性，说明 BCR-ABL 驱动的 Hsp70-Bim PPI 通过富含三种途径的肿瘤客户蛋白来保护 CML：eIF2 信号传导、eIF4E 和 p70S6K 信号传导的调节以及mTOR 信号通路。此外，随着 K562 细胞系中不依赖于 BCR-ABL 的 TKI 耐药性的增加，S1g-2 的致死率逐渐增强，并且在来自不依赖于 BCR-ABL 的 TKI 耐药患者的原始样本中比来自 TKI 敏感患者的原始样本中更有效。通过比较 S1g-2、MKT-077 和 ATP 竞争性 Hsp70 抑制剂 VER-155008 的基本机制，Hsp70-Bim PPI 被确定为 CML 特异性靶点，可通过上述三种致癌信号通路保护免受 TKI 的侵害。 S1g-2 的体内抗 CML 活性和低毒性使其成为治疗 TKI 敏感和耐药 CML 的一流候选药物。
Herein, we screened a novel inhibitor of the Hsp70-Bim protein-protein interaction (PPI), S1g-2, from a Bcl-2 inhibitor library; this compound specifically disrupted the Hsp70-Bim PPI by direct binding to an unknown site adjacent to that of an allosteric Hsp70 inhibitor MKT-077, showing binding affinity in sub-mu M concentration range. S1g-2 exhibited overall 5-10-fold higher apoptosis-inducing activity in CML cells, primary CML blasts, and BCR-ABL-transformed BaF3 cells than other cancer cells, normal lymphocytes, and BaF3 cells, illustrating Hsp70-Bim PPI driven by BCR-ABL protects CML through oncoclient proteins that enriched in three pathways: eIF2 signaling, the regulation of eIF4E and p70S6K signaling, and the mTOR signaling pathways. Moreover, S1g-2 progressively enhanced lethality along with the increase in BCR-ABL-independent TKI resistance in the K562 cell lines and is more effective in primary samples from BCR-ABL-independent TKI-resistant patients than those from TKI-sensitive patients. By comparing the underlying mechanisms of S1g-2, MKT-077, and an ATP-competitive Hsp70 inhibitor VER-155008, the Hsp70-Bim PPI was identified to be a CML-specific target to protect from TKIs through the above three oncogenic signaling pathways. The in vivo activity against CML and low toxicity endows S1g-2 a first-in-class promising drug candidate for both TKI-sensitive and resistant CML.