Exploiting the “Hot-Spots” of Hsp70–Bim Protein–Protein Interaction to Optimize the 1-Oxo-1H-phenalene-2,3-dicarbonitrile Analogues as Specific Hsp70–Bim Inhibitors,Journal of Medicinal Chemistry

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Exploiting the “Hot-Spots” of Hsp70–Bim Protein–Protein Interaction to Optimize the 1-Oxo-1H-phenalene-2,3-dicarbonitrile Analogues as Specific Hsp70–Bim Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-27 , DOI: 10.1021/acs.jmedchem.3c01783
Ziqian Wang ₁ , Hong Zhang ₁ , Xin Li ₁ , Yang Song ₂ , Yuying Wang ₃ , Zhiyuan Hu ₃ , Qishuang Gao ₁ , Maojun Jiang ₁ , Fangkui Yin ₁ , Linjie Yuan ₁ , Jingjing Liu ₃ , Ting Song ₁ , Shaohua Lu ₁ , Guanghong Xu ₁ , Zhichao Zhang ₁

Affiliation

Selectively targeting the cancer-specific protein–protein interaction (PPI) between Hsp70 and Bim has been discovered as a promising strategy for treating chronic myeloid leukemia (CML). The first Hsp70–Bim PPI inhibitor, S1g-2, has been identified to overcome the on-target toxicity of known Hsp70 inhibitors when it induces apoptosis of CML cells. Herein, we carried out a hit-to-lead optimization of S1g-2, yielding S1g-10, which exhibited a 10-fold increase in Hsp70/Bim suppressing potency. Furthermore, S1g-10 not only exhibited a 5- to 10-fold stronger antitumor activity in the sub-μM range against CML cells than S1g-2 in vitro, but it also overcame BCR-ABL-independent tyrosine kinase inhibitor resistance in CML in vivo depending on the Hsp70–Bim signaling pathway. Moreover, through structure–activity relationship analysis, TROSY-HSQC NMR, molecular dynamics simulation, and point mutation validation, two hydrophobic pockets composed of eight key residues were demonstrated to produce predominant interactions with either Bim or S1g-10, regarded as the “hot-spots” in the Hsp70–Bim PPI interface.

中文翻译：

利用 Hsp70-Bim 蛋白质-蛋白质相互作用的“热点”来优化 1-Oxo-1H-phenalene-2,3-dicarbonitrile 类似物作为特异性 Hsp70-Bim 抑制剂

选择性靶向 Hsp70 和 Bim 之间的癌症特异性蛋白-蛋白相互作用 (PPI) 已被发现是治疗慢性粒细胞白血病 (CML) 的一种有前景的策略。第一个 Hsp70 – Bim PPI 抑制剂S1g-2已被确定可以克服已知 Hsp70 抑制剂在诱导 CML 细胞凋亡时的靶向毒性。在此，我们对S1g-2进行了从命中到先导的优化，产生了S1g-10 ，其 Hsp70/Bim 抑制效力提高了 10 倍。此外，在体外， S1g-10不仅在亚μM范围内对CML细胞表现出比S1g-2强5至10倍的抗肿瘤活性，而且还克服了CML中不依赖于BCR-ABL的酪氨酸激酶抑制剂耐药性。体内依赖于 Hsp70 – Bim 信号通路。此外，通过结构-活性关系分析、TROSY-HSQC NMR、分子动力学模拟和点突变验证，由八个关键残基组成的两个疏水口袋被证明与被视为“热点”的 Bim 或S1g-10产生主要相互作用。 Hsp70 – Bim PPI 界面中的“-spots”。

更新日期：2023-11-27

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