JG-98, an allosteric heat shock protein 70 (Hsp70) inhibitor which shows anti-cancer activities affecting both cancer cells and tumor-associated macrophages.
Heat shock protein 70 (Hsp70) is an ATP-dependent molecular chaperone that plays essential roles in protein homeostasis. These chaperones bind and stabilize a wide array of proteins, including many kinases and transcription factors involved in pro-survival signaling. Accordingly, high levels of Hsp70s are associated with immortalized cells and poor prognosis in multiple types of cancer, including breast cancer, endometrial cancer, and cervical cancer. JG-98, an allosteric Hsp70 inhibitor, has antiproliferative activity against cancer cell lines through its ability to inhibit members of the Hsp70 family of molecular chaperones. JG-98 exhibited activity against the breast cancer cell lines MDA-MB-231 and MCF-7 with EC50 values of 0.4 ± 0.03 and 0.7 ± 0.2 μM, respectively. After MDA-MB-231 cells were treated with JG-98 for 48 h, both apoptotic mediators (caspase-3 and PARP) were activated, suggesting that JG-98 triggers apoptosis. Treatment of both MDA-MB-231 and MCF7 cells with JG-98 strongly affected autophagic flux, as indicated by an increase in p62 oligomerization and a reduction in p62 monomer[1]. JG-98 strongly inhibited the interactions between Hsp70 and Bag3, with an IC50 value of 1.6 ± 0.3 μM. JG-98 was a good inhibitor of the Hsp70-Bag1 and Hsp70-Bag2 complexes, with IC50 values of 0.6 ± 0.1 and 1.2 ± 0.1 μM, respectively. Hsp70 was immunoprecipitated from HeLa cells in the presence of JG-98 (50 μM) to test if JG-98 could disrupt the Hsp70-Bag3 interaction in cells. JG-98 reduced the Hsp70-Bag3 interaction by ~ 60%. JG-98 (3 mg/kg) suppressed tumor growth in a HeLa xenograft model[2].
作用机制
JG-98 bound to a conserved, allosteric site on Hsp70 (residues I142, F148, D222, T223, and H224)[1].
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