Evofosfamide (TH-302)
Catalog No.S2757 Synonyms: Evofosfamide
Molecular Weight(MW): 449.04
TH-302 is selective hypoxia-activated prodrug targeting hypoxic regions of solid tumors with IC50 of 19 nM, demonstrates 270-fold enhanced cytotoxicity under hypoxia versus their potency under aerobic conditions, stable to cytochrome P450 metabolism.
Cited by 1 publication
Purity & Quality Control
Biological Activity
| Description | TH-302 is selective hypoxia-activated prodrug targeting hypoxic regions of solid tumors with IC50 of 19 nM, demonstrates 270-fold enhanced cytotoxicity under hypoxia versus their potency under aerobic conditions, stable to cytochrome P450 metabolism. | ||||||||||||||||||||||||||||||
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| 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] |
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| Cell Data |
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| 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] |
Protocol
| Cell Research:[1] |
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| Animal Research:[4] |
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Solubility (25°C)
| In vitro | DMSO | 90 mg/mL (200.42 mM) |
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| Ethanol | 90 mg/mL (200.42 mM) | |
| Water | 10 mg/mL warmed (22.26 mM) | |
| In vivo | Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 30% propylene glycol, 5% Tween 80, 65% D5W For best results, use promptly after mixing. |
30 mg/mL |
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Information
| Molecular Weight | 449.04 |
|---|---|
| Formula | C9H16Br2N5O4P |
| CAS No. | 918633-87-1 |
| Storage | powder |
| in solvent | |
| Synonyms | Evofosfamide |
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Clinical Trial Information
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|---|
| NCT02020226 | Unknown status | Drug: TH-302 | Solid Tumors | Threshold Pharmaceuticals | November 2013 | Phase 1 |
| NCT01833546 | Completed | Drug: Evofosfamide|Drug: Gemcitabine | Solid Tumor|Pancreatic Cancer | Merck KGaA Darmstadt Germany|Threshold Pharmaceuticals | April 18 2013 | Phase 1 |
| NCT01381822 | Unknown status | Drug: TH-302 | Advanced Renal Cell Carcinoma|Gastrointestinal Stromal Tumors|Pancreatic Neuroendocrine Tumors | Threshold Pharmaceuticals | June 2011 | Phase 1 |
| NCT01149915 | Completed | Drug: TH-302 | Acute Myelogenous Leukemia|Acute Lymphoblastic Leukemia|Chronic Myelogenous Leukemia|High-risk Myelodysplastic Syndrome|Chronic Lymphocytic Leukemia|Advanced Myelofibrosis | Threshold Pharmaceuticals | June 2010 | Phase 1 |
| NCT00743379 | Completed | Drug: TH-302 | Non-Small Cell Lung Cancer|Prostate Cancer|Pancreatic Cancer | Threshold Pharmaceuticals | August 2008 | Phase 1|Phase 2 |
| NCT00742963 | Completed | Drug: TH-302 | Soft Tissue Sarcoma | Threshold Pharmaceuticals | August 2008 | Phase 1|Phase 2 |
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