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<p>Heat shock protein 70 (Hsp70) family proteins play a critical role in chronic myeloid leukemia (CML) cells’ survival. Based on the Hsp70 inhibitor JG-98, we developed a new class of inhibitors <i>via</i> a scaffold-hopping strategy. A “privileged structure” in medicinal chemistry replaces the benzothiazole group of JG-98. Through optimization, structure-activity relationship (SAR) analysis, and molecular docking, we gained compounds Q<b>3</b> and Q<b>4</b>, which achieved the same level of ATPase activity inhibition of mitochondrial Hsp70, GRP75, as JG-98. They exhibit a lower molecular weight than JG-98. Q<b>3</b> and Q<b>4</b> maintain a comparable cytotoxic activity with JG-98 against the CML cell line, K562 cells.</p>

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Rational Design and Synthesis of Novel Allosteric Hsp70 Inhibitors via a Scaffold-hopping Strategy

  • 期刊论文

  • 发表日期：

    2026年6月2日

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  • Siyao Wang,
  • Zheming Wang,
  • Zhijue Sheng,
  • Hong Zhang,
  • Ting Song,
  • Yang Song,
  • Ziqian Wang,
  • Zhichao Zhang

摘要

Heat shock protein 70 (Hsp70) family proteins play a critical role in chronic myeloid leukemia (CML) cells’ survival. Based on the Hsp70 inhibitor JG-98, we developed a new class of inhibitors via a scaffold-hopping strategy. A “privileged structure” in medicinal chemistry replaces the benzothiazole group of JG-98. Through optimization, structure-activity relationship (SAR) analysis, and molecular docking, we gained compounds Q3 and Q4, which achieved the same level of ATPase activity inhibition of mitochondrial Hsp70, GRP75, as JG-98. They exhibit a lower molecular weight than JG-98. Q3 and Q4 maintain a comparable cytotoxic activity with JG-98 against the CML cell line, K562 cells.