A4387-10mg | VER 155008 [1134156-31-2] Biotrend

Background

VER 155008 is a potent inhibitor of heat shock protein 70 (Hsp70) family of chaperones, which have been shown to contribute to cancer cell survival via anti-apoptotic functions, that inhibits Hsp70 (with the value of 50% inhibition concentration IC₅₀ of 0.5 μM) as well as heat shock cognate 71 kDa protein (Hsc70) and 78 kDa glucose-regulated protein (Grp78) but to a lesser extent. X-ray crystallography analysis reveals that VER 155008 binds to the ATPase pocket of Hsp70 leading to the inhibition of the intrinsic ATPase activity of Hsp70. Study results also have demonstrated that VER 155008 induces cell proliferation and apoptosis in human cancer cell lines.

Reference

Massey AJ, Williamson DS, Browne H, Murray JB, Dokurno P, Shaw T, Macias AT, Daniels Z, Geoffroy S, Dopson M, Lavan P, Matassova N, Francis GL, Graham CJ, Parsons R, Wang Y, Padfield A, Comer M, Drysdale MJ, Wood M. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol. 2010; 66(3): 535-545

Product Citation

1. Haiyang Yu, Shan Lu, et al. "TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli." bioRxiv. March 29, 2020.
2. Marrugal á, Ferrer I, et al. "Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry." Cells. 2019 Jul 31;8(8). pii: E806. PMID:31370342
3. He XM, Liu L, et al. "HSC70 from Haemaphysalis flava (Acari: Ixodidae) exerts anticoagulation activity in vitro." Ticks Tick Borne Dis. 2018 Oct 17. pii: S1877-959X(18)30258-9. PMID:30366643
4. Santarriaga S, Haver HN, et al. "SRCP1 Conveys Resistance to Polyglutamine Aggregation." Mol Cell. 2018 Jul 19;71(2):216-228.e7. PMID:30029002
5. XiChuan Tanga, LiWei Tanb, et al. "Gold nanorods together with HSP inhibitor-VER-155008 micelles for colon cancer mild-temperature photothermal therapy." Acta Pharmaceutica Sinica B Available online 5 June 2018.
6. Tang, Pei-Ciao, et al. "Proteomic identification of hair cell repair proteins in the model sea anemone Nematostella vectensis." Hearing research (2015). PMID:26183436

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Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	556.4
Cas No.	1134156-31-2
Formula	C₂₅H₂₃Cl₂N₇O₄
Synonyms	adenosine-derived inhibitor, VER155008, VER-155008
Solubility	≥27.8 mg/mL in DMSO; insoluble in H2O; ≥4.65 mg/mL in EtOH with gentle warming and ultrasonic
Chemical Name	4-[[(2R,3S,4R,5R)-5-[6-amino-8-[(3,4-dichlorophenyl)methylamino]purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methoxymethyl]benzonitrile
SDF	Download SDF
Canonical SMILES	C1=CC(=CC=C1COCC2C(C(C(O2)N3C4=C(C(=NC=N4)N)N=C3NCC5=CC(=C(C=C5)Cl)Cl)O)O)C#N
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Kinase experiment [1,2]:
Hsc70, Hsp70 and Grp78 fluorescence polarisation (FP) assay	The FP assay for Hsp70 was conducted in aqueous buffer consisting of 100 mM Tris pH 7.4, 150 mM KCl and 5 mM CaCl2, in a final assay volume of 100 uL, using 96-well black polystyrene high bind plates with a Fusion plate reader. N6-(6-amino)hexyl-ATP-5-FAM and the in-house protein preparation of GST-HSP70 3-382 had final concentrations in the assay of 20 nM and 400 nM, respectively. Compounds were tested as 10-point IC50, with a final DMSO concentration of 5%. Assay mixtures were incubated for 3 hrs prior to reading on the Fusion (ex 485 nm; em 535 nm). The data was fitted using a 4 parameter logistical data model by XLFit 4. The FP assay for Hsc70 and Grp78 was carried out as described for Hsp70 using the same N6-(6-amino)hexyl-ATP-5-FAM as the FP probe with the following modifications. For Hsc70, the protein and probe concentrations were 0.3 μM and 20 nM, respectively, with a 30 min incubation at 22 ℃ while for Grp78, the protein and probe concentrations were 2 μM and 10 nM, respectively, with a 2 hr incubation at 22 ℃. The KD for the FAM-ATP probe was 0.24 μM for Hsc70 and 2 μM for Grp78.
Cell experiment [1]:
Cell lines	BT474, MB-468, HCT116 and HT29 cells
Preparation method	The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months.
Reaction Conditions	50 μM; 72 hrs
Applications	In human breast and colon cancer cell lines BT474, MB-468, HCT116 and HT29, VER 155008 inhibited cell proliferation, with the GI50 values ranging from 5.3 μM to 14.4 μM. In addition, VER 155008 induced Hsp90 client protein degradation in both HCT116 and BT474 cells.
Animal experiment [1]:
Animal models	Mice bearing HCT116 tumors
Dosage form	25 or 40 mg/kg; i.v.
Applications	In mice bearing HCT116 tumors, VER 155008 showed rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Massey AJ, Williamson DS, Browne H, Murray JB, Dokurno P, Shaw T, Macias AT, Daniels Z, Geoffroy S, Dopson M, Lavan P, Matassova N, Francis GL, Graham CJ, Parsons R, Wang Y, Padfield A, Comer M, Drysdale MJ, Wood M. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol. 2010; 66(3): 535-545 [2]. Williamson DS, Borgognoni J, Clay A, Daniels Z, Dokurno P, Drysdale MJ, Foloppe N, Francis GL, Graham CJ, Howes R, Macias AT, Murray JB, Parsons R, Shaw T, Surgenor AE, Terry L, Wang Y, Wood M, Massey AJ. Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J Med Chem. 2009 Mar 26;52(6):1510-3.