Product Categories

TH-302

TH-302 is selective hypoxia-activated prodrug targeting hypoxic regions of solid tumors with IC50 of 19 nM.

Catalog No.S2757
Availability

The item is temporarily out of stock. Please leave your email address and we will inform you when we have it in stock.

Just click the ‘Arrival Notice’ and leave your email address to get 10% off.

Arrival Notice
Tel: +1-832-582-8158[email protected]

TH-302 Chemical Structure
Molecular Weight: 449.04

Product Information

  • Compare P450 (e.g. CYP17) Inhibitors
    Compare P450 (e.g. CYP17) Inhibitors

Product Description

Biological Activity Protocol Chemical Information Tech Support & FAQs

Biological Activity

Description TH-302 is selective hypoxia-activated prodrug targeting hypoxic regions of solid tumors with IC50 of 19 nM.
Targets Hypoxic regions
IC50 19 nM [1]
In vitro TH-302 is selectively potent under hypoxia and stable to liver microsomes. Substitution of the chlorine with bromine on the phosphorus mustard in 3b increases the potency by 10-fold and maintaines the high hypoxic selectivity [Hypoxia cytotoxicity ratio (HCR) = 270]. In both human lung cancer H460 cells and human colon cancer HT29 cells, potent cytotoxicity of TH-302 is observed under N2. TH-302 inhibits H460 cells and HT29 cells with IC90 of 0.1 μM and 0.2 μM, respectively. [1] TH-302 shows much enhanced potency in H460 spheroids compared to H460 monolayer cells under normoxia. [2] TH-302 exhibits potent cytotoxicity to MM cells with hypoxic selectivity and dose dependency. TH-302 can induce G0/G1 cell-cycle arrest under hypoxic conditions. The effect of TH-302 on cell-cycle machinery is mediated by down-regulating cyclin D1/2/3, CDK4/6, p21cip-1, p27kip-1, and pRb expression, whereas CDK2 expression remained undisturbed. TH-302 can induce dose-dependent apoptosis in both human and murine MM cells in hypoxic conditions. TH-302-activated apoptosis is mediated through down-regulating the antiapoptotic proteins BCL-2 and BCL-xL, as well as up-regulating the expression of cleaved proapoptotic protein caspase-3, -8, and -9 and poly ADP-ribose polymerase. In contrast to the hypoxia-specific toxicity, TH-302 shows very low toxicity in normoxic condition, even at high concentrations. [3]
In vivo TH302 inhibits primary tumor growth by 41% on day 25 after implantation, whereas TH302 plus gemcitabine (a nucleoside analog) inhibits primary tumor growth by 96% on day 25. [1] When TH-302 is administered at 6.25, 12.5, 25, or 50 mg/kg in the H460 NSCLC xenograft model QD × 5/wk × 2 wks (once a day for 5 days per week for 2 weeks) i.p., the tumor growth inhibition at Day 22 is 43%, 51%, 75%, and 89%, respectively. TH-302 at 100 mg/kg shows a decrease in blood cell counts 3 days after treatment end, but is totally recovered 7 days post-treatment. TH-302 under all tested regimens exhibits efficacy metrics ranging from 58% to 89% tumor growth inhibition. TH-302 induced cell killing is breathing oxygen concentration dependent, with the greatest cytotoxicity occurring when the tumor-bearing mice are exposed to low oxygen concentrations. Tumor growth is significantly reduced by TH-302 in animals breathing 10% O2 compared with 95% O2 breathing. After TH-302 treatment, the pimonidazole-positive area is significantly decreased at 48 hours after dosing (6.3 % in vehicle vs. 1.8 % in the TH-302 treatment group). [4]
Clinical Trials TH-302 has entered a phase II clinical trial for the treatment of soft tissue sarcoma.
Features

Protocol(Only for Reference)

Cell Assay: [1]

Cell lines Human H460 or HT29 cells
Concentrations 0.01 -1 μM
Incubation Time 2 hours
Method Exponentially growing human H460 or HT29 cells are seeded into 60 mm notched glass plates at 3 × 105 cells per plate and grown in RPMI medium supplemented with 10% fetal bovine serum for 2 days prior to initiating treatment. On the day of the test, TH-302 stocks of known concentrations are prepared in complete medium and 2 mL of the desired stock is added to each plate. The plates are placed in either an anaerobic chamber or a standard tissue-culture incubator. The anaerobic chamber is evacuated and gassed with the anaerobic gas mixture (90% N2/5% CO2/5% H2) to create a hypoxic environment. Cells are then incubated with TH-302 for 2 hours at 37 °C. At the end of treatment, plates are removed from each vessel and washed with phosphate-buffered saline and a solution of trypsin-EDTA and then trypsinized for 5 min at 37 °C. Detached cells are neutralized with medium plus serum and spun for 5 min at 100g. Cells are resuspended at approximately 1 × 106 cells/mL and diluted 10-fold for plating. The exact concentration of each stock is determined. Known numbers of cells are plated and placed undisturbed in an incubator for between 9 and 13 days. Colonies are fixed and stained with a solution of 95% ethanol with 0.25% crystal violet stain. Colonies of greater than 50 cells are counted, and the surviving fraction is determined. Plating efficiencies (PEs) are determined by dividing the number of colonies by the actual number of cells plated. Surviving fractions are calculated by dividing the PEs of treated cells by the PEs of untreated cells.

Animal Study: [4]

Animal Models H460, Calu-6, PC-3, H82, A375, Stew2, 786-O, PLC/PRF/5, Hs766t, BxPC-3, and SU.86.86 xenografts are established in NCI SCID female mice.
Formulation Saline
Dosages 50 mg/kg
Administration Intraperitoneally
1

References

Chemical Information

Download TH-302 SDF
Molecular Weight (MW) 449.04
Formula

C9H16Br2N5O4P
CAS No. 918633-87-1
Synonyms N/A
Storage 2 years -20°CPowder
2 weeks4°Cin DMSO
6 months-80°Cin DMSO
Chemical Name (1-methyl-2-nitro-1H-imidazol-5-yl)methyl N,N-bis(2-bromoethyl)phosphordiamidate
Molarity Calculator Dilution Calculator Molecular Weight Calculator

Research Area

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions
Tel: +1-832-582-8158 Ext:3Monday–Friday 9:00 AM–5:00 PM (Central Time)

If you have any other enquiries, please leave a message.

* Indicates a Required Field

Related P450 (e.g. CYP17) Inhibitors

  • TAK-700 (Orteronel)

    TAK-700 (Orteronel) is a potent and highly selective rat and human 17,20-lyase inhibitor with IC50 of 54 nM and 38 nM, respectively.

  • Cyproterone acetate

    Cyproterone acetate is an androgen receptor (AR) antagonist with IC50 of 7.1 nM.

  • Avasimibe(CI-1011)

    Avasimibe inhibits ACAT and CYP2C9 with IC50 of 3.3 μM and 2.9 μM, respectively.

  • Alizarin

    Alizarin strongly inhibits P450 isoform CYP1A1, CYP1A2 and CYP1B1 with IC50 of 6.2 μM, 10.0 μM and 2.7 μM, respectively.

  • Galeterone (TOK-001)

    Galeterone (TOK-001, VN/124-1) is a selective CYP17 inhibitor and androgen receptor (AR) antagonist with IC50 of 300 nM and 384 nM, respectively.

  • PF-4981517

    PF-4981517 is a potent and selective inhibitor of CYP3A4 (P450) with IC50 of 0.03 μM.

  • Varespladib (LY315920)

    LY315920 (Varespladib) is a potent and selective secretory phospholipase A2 (sPLA) inhibitor with IC50 of 7 nM.

  • MK-8245

    MK-8245 is an inhibitor of stearoyl-CoA desaturase (SCD) which targets the liver with IC50 of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1.

  • Tipifarnib (Zarnestra)

    Tipifarnib (Zarnestra, R115777) is a potent and specific farnesyltransferase (FTase) inhibitor with IC50 of 0.6 nM.

  • Cilomilast (SB-207499)

    Cilomilast (SB-207499) is a potent LPDE4 and HPDE4 inhibitor with IC50 of 100 nM and 120 nM, respectively.

Recently Viewed Items

Tags: buy TH-302 | TH-302 supplier | purchase TH-302 | TH-302 cost | TH-302 manufacturer | order TH-302 | TH-302 distributor
Contact Us