Name: Evofosfamide (TH-302)
Brand: Selleck Chemicals
SKU: S2757
Rating: 5 (6 reviews)

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Controllo Qualità (Quality Control)

Lotto: Purezza: 99.82%

99.82

Target correlati	PROTAC Dyes Antineoplastic and Immunosuppressive Antibiotics ADC Cytotoxin Selection Antibiotics for Transfected Cell Antibiotics for Mammalian Cell Culture ADC Linker Molecular Glues Hydrotropic Agents Antibiotics for Plant Cell Culture
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Coltura cellulare, trattamento e concentrazione di lavoro
(Cell Culture, Treatment & Working Concentration)

Linee cellulari	Tipo di saggio	Tempo di incubazione	Descrizione dell'attività	PMID
H460	Cytotoxicity assay	2 hrs	Cytotoxicity against human H460 cells under hypoxic condition after 2 hrs by Alamar blue staining assay, IC50=0.019μM.	18257544
H460	Cytotoxicity assay	2 hrs	Cytotoxicity against human H460 cells under hypoxic condition after 2 hrs by clonogenic assay, IC90=0.1μM.	18257544
HT29	Cytotoxicity assay	2 hrs	Cytotoxicity against human HT29 cells under hypoxic condition after 2 hrs by clonogenic assay, IC90=0.2μM.	18257544
H460	Cytotoxicity assay	2 hrs	Cytotoxicity against human H460 cells under normoxic condition after 2 hrs by Alamar blue staining assay, IC50=5.1μM.	18257544
H460	Cytotoxicity assay	2 hrs	Cytotoxicity against human H460 cells under normoxic condition after 2 hrs by clonogenic assay, IC90=30μM.	18257544
HT29	Cytotoxicity assay	2 hrs	Cytotoxicity against human HT29 cells under normoxic condition after 2 hrs by clonogenic assay, IC90=40μM.	18257544
NCI-H460	Cytotoxicity assay	24 hrs	Cytotoxicity against human NCI-H460 cells pretreated for 24 hrs under hypoxic condition followed by compound washout measured after 72 hrs by MTT assay, IC50=9.08μM.	28350997
HT-29	Cytotoxicity assay	24 hrs	Cytotoxicity against human HT-29 cells pretreated for 24 hrs under hypoxic condition followed by compound washout measured after 72 hrs by MTT assay, IC50=49.51μM.	28350997
NCI-H460	Cytotoxicity assay	24 hrs	Cytotoxicity against human NCI-H460 cells after 24 hrs under hypoxic condition by luminescence-based Cell-Titer Glo assay, IC50=0.0093μM.	29079474
NCI-H460	Cytotoxicity assay	24 hrs	Cytotoxicity against human NCI-H460 cells after 24 hrs under normoxic condition by luminescence-based Cell-Titer Glo assay, IC50=6.65μM.	29079474
DU145	Cytotoxicity assay	2 hrs	Cytotoxicity against human DU145 cells incubated for 2 hrs under hypoxic condition measured after 72 hrs by Alamar blue assay, IC50=4.14μM.	29259746
PC3	Cytotoxicity assay	2 hrs	Cytotoxicity against human PC3 cells incubated for 2 hrs under hypoxic condition measured after 72 hrs by Alamar blue assay, IC50=6.49μM.	29259746
HEMC-SS	Antiproliferative assay	24 hrs	Antiproliferative activity against human HEMC-SS cells treated for 24 hrs under hypoxic condition followed by compound wash-out and incubated under normoxic condition for 48 hrs by alamar blue assay, IC50=0.13μM.	30199705
HEMC-SS	Antiproliferative assay	24 hrs	Antiproliferative activity against human HEMC-SS cells treated for 24 hrs under normoxic condition followed by compound wash-out and incubated under normoxic condition for 48 hrs by alamar blue assay, IC50=2.9μM.	30199705
NCI-H460	Antiproliferative assay		Antiproliferative activity against human NCI-H460 cells in presence of N2, IC50=2μM.	30295477
NCI-H460	Antiproliferative assay		Antiproliferative activity against human NCI-H460 cells in presence of O2, IC50=25μM.	30295477
MDA-MB-468	Cytotoxicity assay	4 hrs	Cytotoxicity against human MDA-MB-468 cells incubated for 4 hrs under hypoxic condition followed by compound washout and measured after 5 days by SRB assay, IC50=0.0062μM.	30885680
SW620	Cytotoxicity assay	4 hrs	Cytotoxicity against human SW620 cells incubated for 4 hrs under hypoxic condition followed by compound washout and measured after 5 days by SRB assay, IC50=0.052μM.	30885680
MDA-MB-468	Cytotoxicity assay	4 hrs	Cytotoxicity against human MDA-MB-468 cells incubated for 4 hrs under aerobic condition followed by compound washout and measured after 5 days by SRB assay, IC50=4.403μM.	30885680
SW620	Cytotoxicity assay	4 hrs	Cytotoxicity against human SW620 cells incubated for 4 hrs under aerobic condition followed by compound washout and measured after 5 days by SRB assay, IC50=20.6μM.	30885680
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Informazioni chimiche, conservazione e stabilità (Chemical Information, Storage & Stability)

Peso molecolare	449.04	Formula	C₉H₁₆Br₂N₅O₄P	Conservazione (Dalla data di ricezione)	3 anni-20°Cpolvere
N. CAS	918633-87-1	Scarica SDF		Conservazione delle soluzioni stock	1 anno-80°Cin solvente 1 mese-20°Cin solvente

Solubilità (Solubility)

In vitro
Lotto:

DMSO : 90 mg/mL (200.42 mM)
(Il DMSO contaminato da umidità può ridurre la solubilità. Utilizzare DMSO fresco e anidro.)

Ethanol : 90 mg/mL

Water : 10 mg/mL

Calcolatore di Molarità

Massa	Concentrazione	Volume	Peso molecolare
=	×	×

Calcolatore di Diluizione Calcolatore del Peso Molecolare

In vivo Lotto:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	30%propylene glycol 1 5%Tween80 2 65%D5W Validato dai laboratori Selleck. Se necessiti di modifiche a questa formulazione, contatta il nostro team di vendita per test personalizzati.	30.000mg/ml (66.81mM)	Taking the 1 mL working solution as an example, add 300 μL of 100 mg/ml clarified propylene glycol stock solution to 50 μL of Tween 80, mix evenly to clarify it; then continue to add 650 μL of D5W to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

Calcolatore di formulazione in vivo (Soluzione chiara)

Passo 1: Inserire le informazioni di seguito (Consigliato: Un animale aggiuntivo per tenere conto della perdita durante l'esperimento)

Dosaggio: mg/kg Peso medio degli animali: g Volume di dosaggio per animale:μL Numero di animali:

Passo 2: Inserire la formulazione in vivo (Questo è solo il calcolatore, non la formulazione. Contattateci prima se non c'è una formulazione in vivo nella sezione Solubilità.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Risultati del calcolo:

Concentrazione di lavoro: mg/ml;

Metodo per preparare il liquido master di DMSO: mg farmaco predissolto in μL DMSO ( Concentrazione del liquido master mg/mL, Vi preghiamo di contattarci prima se la concentrazione supera la solubilità del DMSO del lotto del farmaco. )

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungereμL PEG300, mescolare e chiarire, quindi aggiungereμL Tween 80, mescolare e chiarire, quindi aggiungere μL ddH₂O, mescolare e chiarire.

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungere μL Olio di mais, mescolare e chiarire.

Nota: 1. Si prega di assicurarsi che il liquido sia limpido prima di aggiungere il solvente successivo.
2. Assicurarsi di aggiungere il/i solvente/i in ordine. È necessario assicurarsi che la soluzione ottenuta, nell'aggiunta precedente, sia una soluzione limpida prima di procedere all'aggiunta del solvente successivo. Metodi fisici come il vortex, gli ultrasuoni o il bagno d'acqua calda possono essere utilizzati per facilitare la dissoluzione.

Meccanismo d'azione (Mechanism of Action)

In vitro	Evofosfamide (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 this compound is observed under N₂. It inhibits H460 cells and HT29 cells with IC90 of 0.1 μM and 0.2 μM, respectively. It shows much enhanced potency in H460 spheroids compared to H460 monolayer cells under normoxia. This compound exhibits potent cytotoxicity to MM cells with hypoxic selectivity and dose dependency. It can induce G0/G1 cell-cycle arrest under hypoxic conditions. The effect of it 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. It 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, it shows very low toxicity in normoxic condition, even at high concentrations.
In vivo	Evofosfamide (TH-302) inhibits primary tumor growth by 41% on day 25 after implantation, whereas this compound plus a nucleoside analog inhibits primary tumor growth by 96% on day 25. When 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., it shows tumor growth inhibition at Day 22 of 43%, 51%, 75%, and 89%, respectively. At 100 mg/kg, it causes a decrease in blood cell counts 3 days after treatment end, but these are totally recovered 7 days post-treatment. Under all tested regimens, it exhibits efficacy metrics ranging from 58% to 89% tumor growth inhibition. Its 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 this compound in animals breathing 10% O₂ compared with 95% O₂ breathing. After 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).
Riferimenti	[1] https://pubmed.ncbi.nlm.nih.gov/18257544/ [2] https://pubmed.ncbi.nlm.nih.gov/22147748/ [3] https://pubmed.ncbi.nlm.nih.gov/20530289/ [4] https://pubmed.ncbi.nlm.nih.gov/22184053/

Informazioni sullo studio clinico (Clinical Trial Information)

(dati da https://clinicaltrials.gov, aggiornato il 2024-05-22)

Numero NCT	Reclutamento	Condizioni	Sponsor/Collaboratori	Data di inizio	Fasi
NCT02020226	Unknown status	Solid Tumors	Threshold Pharmaceuticals	November 2013	Phase 1
NCT01833546	Completed	Solid Tumor\|Pancreatic Cancer	Merck KGaA Darmstadt Germany\|Threshold Pharmaceuticals	April 18 2013	Phase 1

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Evofosfamide (TH-302)

Peso molecolare: 449.04