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JG-98 Sale

(Synonyms: 3-苄基-2-((Z)-((E)-5-(6-氯-3-甲基苯并[D]噻唑-2(3H)-亚基)-3-乙基-4-氧代噻唑啉-2-亚基)甲基)噻唑-3-鎓氯化物) 目录号 : GC34634

JG-98 is an allosteric inhibitor of Hsp70 that binds tightly to a deep pocket that is conserved in members of the Hsp70 family. JG-98 induces classical apoptosis features, including morphological changes consistent with programmed cell death and positive annexin staining. JG-98 exhibits anticancer activity.

JG-98 Chemical Structure

Cas No.:1456551-16-8

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产品描述

JG-98 is an allosteric inhibitor of Hsp70 that binds tightly to a deep pocket that is conserved in members of the Hsp70 family. JG-98 induces classical apoptosis features, including morphological changes consistent with programmed cell death and positive annexin staining. JG-98 exhibits anticancer activity.

[1] Julia A. Yaglom, et al. Scientific Reports. 2018, volume 8, Article number: 3010.

Chemical Properties

Cas No. 1456551-16-8 SDF
别名 3-苄基-2-((Z)-((E)-5-(6-氯-3-甲基苯并[D]噻唑-2(3H)-亚基)-3-乙基-4-氧代噻唑啉-2-亚基)甲基)噻唑-3-鎓氯化物
Canonical SMILES CN1/C(SC2=CC(Cl)=CC=C12)=C3S/C(N(CC)C\3=O)=C\C4=[N+](C=CS4)CC5=CC=CC=C5.[Cl-]
分子式 C24H21Cl2N3OS3 分子量 534.54
溶解度 DMSO : 5 mg/mL (9.35 mM) 储存条件 Store at -20°C
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1 mM 1.8708 mL 9.3538 mL 18.7077 mL
5 mM 0.3742 mL 1.8708 mL 3.7415 mL
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Research Update

Pharmacological inhibition of BAG3-HSP70 with the proposed cancer therapeutic JG-98 is toxic for cardiomyocytes

J Cell Biochem 2022 Jan;123(1):128-141.PMID:34487557DOI:10.1002/jcb.30140.

The co-chaperone Bcl2-associated athanogene-3 (BAG3) maintains cellular protein quality control through the regulation of heat shock protein 70 (HSP70). Cancer cells manipulate BAG3-HSP70-regulated pathways for tumor initiation and proliferation, which has led to the development of promising small molecule therapies, such as JG-98, which inhibit the BAG3-HSP70 interaction and mitigate tumor growth. However, it is not known how these broad therapies impact cardiomyocytes, where the BAG3-HSP70 complex is a key regulator of protein turnover and contractility. Here, we show that JG-98 exposure is toxic in neonatal rat ventricular myocytes (NRVMs). Using immunofluorescence microscopy to assess cell death, we found that apoptosis increased in NRVMs treated with JG-98 doses as low as 10 nM. JG-98 treatment also reduced autophagy flux and altered expression of BAG3 and several binding partners involved in BAG3-dependent autophagy, including SYNPO2 and HSPB8. We next assessed protein half-life with disruption of the BAG3-HSP70 complex by treating with JG-98 in the presence of cycloheximide and found BAG3, HSPB5, and HSPB8 half-lives were reduced, indicating that complex formation with HSP70 is important for their stability. Next, we assessed sarcomere structure using super-resolution microscopy and found that disrupting the interaction with HSP70 leads to sarcomere structural disintegration. To determine whether the effects of JG-98 could be mitigated by pharmacological autophagy induction, we cotreated NRVMs with rapamycin, which partially reduced the extent of apoptosis and sarcomere disarray. Finally, we investigated whether the effects of JG-98 extended to skeletal myocytes using C2C12 myotubes and found again increased apoptosis and reduced autophagic flux. Together, our data suggest that nonspecific targeting of the BAG3-HSP70 complex to treat cancer may be detrimental for cardiac and skeletal myocytes.

Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations

Sci Rep 2018 Feb 14;8(1):3010.PMID:29445088DOI:10.1038/s41598-017-14900-0.

Hsp70 is a promising anti-cancer target. Our JG-98 series of Hsp70 inhibitors show anti-cancer activities affecting both cancer cells and tumor-associated macrophages. They disrupt Hsp70 interaction with a co-chaperone Bag3 and affect signaling pathways important for cancer development. Due to a prior report that depletion of Hsp70 causes similar responses as depletion of Hsp90, interest to Hsp70 inhibitors as drug prototypes is hampered by potential similarity of their effects to effects of Hsp90 inhibitors. Here, using the Connectivity Map platform we demonstrate that physiological effects of JG-98 are dissimilar from effects of Hsp90 inhibitors, thus justifying development of these compounds. Using gene expression and ActivSignal IPAD platform, we identified pathways modulated by JG-98. Some of these pathways were affected by JG-98 in Bag3-dependent (e.g. ERK) and some in Bag3-independent manner (e.g. Akt or c-myc), indicating multiple effects of Hsp70 inhibition. Further, we identified genes that modulate cellular responses to JG-98, developed approaches to predict potent combinations of JG-98 with known drugs, and demonstrated that inhibitors of proteasome, RNApol, Akt and RTK synergize with JG-98. Overall, here we established unique effects of novel Hsp70 inhibitors on cancer cell physiology, and predicted potential drug combinations for pre-clinical development.

Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98

Bioorg Med Chem Lett 2020 Mar 1;30(5):126954.PMID:31952963DOI:10.1016/j.bmcl.2020.126954.

The heat shock protein 70 (Hsp70) family of molecular chaperones are highly expressed in tumors. Inhibitors containing a pyridinium-modified benzothiazole, such as JG-98, bind to a conserved, allosteric site in Hsp70, showing promising anti-proliferative activity in cancer cells. When bound to Hsp70, the charged pyridinium makes favorable contacts; however, this moiety also increases the inhibitor's fluorescence, giving rise to undesirable interference in biochemical and cell-based assays. Here, we explore whether the pyridinium can be replaced with a neutral pyridine. We report that pyridine-modified benzothiazoles, such as compound 17h (JG2-38), have reduced fluorescence, yet retain promising anti-proliferative activity (EC50 values ~0.1 to 0.07 µM) in breast and prostate cancer cell lines. These chemical probes are expected to be useful in exploring the roles of Hsp70s in tumorigenesis and cell survival.

Author Correction: Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations

Sci Rep 2018 May 2;8(1):7177.PMID:29720612DOI:10.1038/s41598-018-24992-x.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2α via the Hsp70-Bag3 module

iScience 2022 Apr 22;25(5):104282.PMID:35573186DOI:10.1016/j.isci.2022.104282.

The major heat shock protein Hsp70 forms a complex with a scaffold protein Bag3 that links it to components of signaling pathways. Via these interactions, the Hsp70-Bag3 module functions as a proteotoxicity sensor that controls cell signaling. Here, to search for pathways regulated by the complex, we utilized JG-98, an allosteric inhibitor of Hsp70 that blocks its interaction with Bag3. RNAseq followed by the pathway analysis indicated that several signaling pathways including UPR were activated by JG-98. Surprisingly, only the eIF2α-associated branch of the UPR was activated, while other UPR branches were not induced, suggesting that the response was unrelated to the ER proteotoxicity and ER-associated kinase PERK1. Indeed, induction of the UPR genes under these conditions was driven by a distinct eIF2α kinase HRI. Hsp70-Bag3 directly interacted with HRI and regulated eIF2α phosphorylation upon cytoplasmic proteotoxicity. Therefore, cytosolic proteotoxicity can activate certain UPR genes via Hsp70-Bag3-HRI-eIF2α axis.