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JG-98, an allosteric heat shock protein 70 (Hsp70) inhibitor, which binds tightly to a conserved site on Hsp70 and disrupts the Hsp70-Bag3 interaction. JG-98 exhibits anticancer properties that impact tumor-associated macrophages as well as cancer cells.
| Targets |
Hsp70
JG-98 (30 nM-30 μM; 72 hours) exhibits antiproliferative activity against a variety of cell lines, with EC50s ranging from approximately 0.3 to 4 μM[2]. JG-98 (10 μM; 48 hours) activates apoptotic mediators (cleavage of PARP and caspase-3 in MDA-MB-231 cells[1]. JG-98 relieves the inhibition of downstream effectors, such as p21 and p27, and destabilizes FoxM1[2]. |
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| ln Vitro |
JG-98 (30 nM-30 μM; 72 hours) exhibits antiproliferative activity against a variety of cell lines, with EC50s ranging from approximately 0.3 to 4 μM[2].
JG-98 (10 μM; 48 hours) activates apoptotic mediators (cleavage of PARP and caspase-3 in MDA-MB-231 cells[1]. JG-98 relieves the inhibition of downstream effectors, such as p21 and p27, and destabilizes FoxM1[2]. JG-98 exhibited antiproliferative activity against breast cancer cell lines MDA-MB-231 and MCF-7 with EC₅₀ values of 0.4 ± 0.03 µM and 0.7 ± 0.2 µM, respectively, as measured by MTT assay. This represents at least a 3-fold improvement in potency compared to the parent compound MKT-077. [1] JG-98 induced apoptosis in MDA-MB-231 cells, as evidenced by the cleavage of caspase-3 and PARP after 48 hours of treatment. [1] JG-98 affected autophagic flux in both MDA-MB-231 and MCF-7 cells, indicated by increased p62 oligomerization and a reduction in p62 monomer levels after 24 hours of treatment. [1] Treatment of cells with a related analogue (JG-83) led to a modest reduction (~25%) in the protein levels of known Hsp70 clients Akt1 and Raf1, and elevated levels of mutated p53 in MCF-7 cells. [1] JG-98 showed improved metabolic stability in mouse liver microsomes with a half-life (t₁/₂) of 37 minutes, which is at least 7-fold longer than that of MKT-077 (t₁/₂ < 5 minutes). [1] JG-98 was titrated into a solution of the nucleotide-binding domain of the bacterial Hsp70 homologue DnaK (DnaK₁₋₃₈₈). NMR chemical shift perturbations indicated that JG-98 binds to a deep, hydrophobic allosteric pocket near residues I142 and F148, a site previously implicated for MKT-077 binding. The perturbed residues are highly conserved in human Hsp70 family members. [1] |
| ln Vivo |
JG-98 (3 mg/kg; intraperitoneally; on days 0, 2, and 4) inhibits the growth of tumors in xenograft models containing HeLa and MCF7 cells[2].
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| Cell Assay |
Cell Line: MCF-7, MDA-MB-231, A375, MeWo, HeLa, HT-29, SKOV3, Jurkat, mouse embryonic fibroblasts (MEF), MM1.R, INA6, RPMI-8226, JJN-3, U266, NCI-H929, L363, MM1.S, KMS11, LP-1, AMO-1, OPM1, OPM2 cells
Concentration: 30 nM-30 μM Incubation Time: 72 hours Result: Active against all of the lines tested, and the EC50s were variable (between ~0.3 μM and 4 μM). Normal MEFs and OPM1 and OPM2 were relatively less sensitive. Antiproliferative activity was assessed using the MTT assay. Cells were seeded in plates, treated with serial dilutions of the compounds, and incubated. Following the incubation period, MTT reagent was added to the wells. After further incubation, the formed formazan crystals were dissolved, and the absorbance was measured. Viability was calculated relative to untreated controls. [1] For analysis of client protein stability and apoptotic markers, cells were treated with compounds for specified durations (e.g., 24 or 48 hours). Cells were then lysed, and proteins were separated by SDS-PAGE, transferred to membranes, and probed with specific primary antibodies against targets such as Akt1, Raf1, p53, cleaved caspase-3, cleaved PARP, p62, Hsp70, and Hsp90. Binding was detected using appropriate secondary antibodies conjugated to a detection system. [1] The binding affinity of biotinylated analogues for Hsc70 was determined by an ELISA. Purified human Hsc70 was immobilized on plates. After blocking, biotinylated compounds were added at varying concentrations. Binding was detected using streptavidin conjugated to a reporting enzyme, followed by substrate addition and absorbance measurement. Apparent dissociation constants (K_D) were calculated from the binding curves. [1] |
| Animal Protocol |
6-week-old NCR mice (xenografts of MCF7 and HeLa cells)
3 mg/kg Intraperitoneal injection; on days 0, 2, and 4 |
| ADME/Pharmacokinetics |
JG-98 showed greater stability in mouse liver microsomal assays, with a half-life (t₁/₂) of 37 minutes, compared to less than 5 minutes for MKT-077. [1]
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| References |
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| Additional Infomation |
JG-98 is an analogue of the allosteric Hsp70 inhibitor MKT-077, designed to overcome its rapid metabolic degradation. Its chemical structure contains a 5-chloro substituent on a benzothiazole ring and a benzyl-substituted 2-thiazole group. [1]
It binds to conserved allosteric sites on Hsp70 family proteins, interfering with molecular chaperone function. [1] This compound is more toxic to cancer cell lines than to normal mouse embryonic fibroblasts (MEF), with a selectivity window estimated to be approximately 8 to 20 times greater based on EC₅₀ comparisons (MEF EC₅₀ = 24 ± 1.3 µM). [1] |
| Molecular Formula |
C24H21CL2N3OS3
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|---|---|
| Molecular Weight |
534.5440
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| Exact Mass |
533.02
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| Elemental Analysis |
C, 53.93; H, 3.96; Cl, 13.26; N, 7.86; O, 2.99; S, 17.99
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| CAS # |
1456551-16-8
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| Related CAS # |
1456551-16-8 (chloride); 1456687-09-4 (cation)
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| PubChem CID |
72547053
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| Appearance |
Yellow to orange solid powder
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
33
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| Complexity |
785
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCN1/C(=C/C2=[N+](C=CS2)CC3=CC=CC=C3)/S/C(=C/4\N(C5=C(S4)C=C(C=C5)Cl)C)/C1=O.[Cl-]
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| InChi Key |
AUPPGWXGMILTRB-HDPAMLMOSA-M
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| InChi Code |
InChI=1S/C24H21ClN3OS3.ClH/c1-3-28-21(14-20-27(11-12-30-20)15-16-7-5-4-6-8-16)32-22(23(28)29)24-26(2)18-10-9-17(25)13-19(18)31-24;/h4-14H,3,15H2,1-2H3;1H/q+1;/p-1/b24-22+;
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| Chemical Name |
(2Z,5E)-2-[(3-benzyl-1,3-thiazol-3-ium-2-yl)methylidene]-5-(6-chloro-3-methyl-1,3-benzothiazol-2-ylidene)-3-ethyl-1,3-thiazolidin-4-one;chloride
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| Synonyms |
JG-98; JG98; JG 98
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 5~10 mg/mL (9.4~18.7 mM）
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8708 mL | 9.3538 mL | 18.7077 mL | |
| 5 mM | 0.3742 mL | 1.8708 mL | 3.7415 mL | |
| 10 mM | 0.1871 mL | 0.9354 mL | 1.8708 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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