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Donafenib (Sorafenib D3; Bay 43-9006 D3; CM-4307; Zepsun), the tri-deuterated (terminal CD3) form of Sorafenib, is a novel, potent and orally bioavailable multikinase inhibitor that has been approved in China (in 2021) for clinical uses to treat patients with unresectable hapatic tumors. It inhibits Raf kinase and receptor tyrosine kinases with potential anticancer acivity. Donafenib was under clinical trials in China in patients with advanced hepatocellular carcinoma (HCC). Sorafenib is a multikinase inhibitor IC50s of 6 nM, 20 nM, and 22 nM for Raf-1, B-Raf, and VEGFR-3, respectively.
| ln Vitro |
Drug compounds have been modified to include stable heavy isotopes of hydrogen, carbon, and other elements. These isotopes are mostly utilized as quantitative tracers during the drug development process. One possible benefit of crepuscular chemicals is their prolonged half-degeneration period. Crepuscular substances have the potential to extend the compound's pharmacokinetic profile, or its future half-life. These drugs' tolerance, safety, and efficacy (2) increase intestinal bioavailability. Deuterated substances have the ability to lessen the amount of undesirable metabolism (first-pass metabolism) in the umbilical cord and intestinal wall, increasing the amount of unmetabolized medication that reaches its intended site of action. Better tolerance and activity at low doses are determined by high bioavailability. (3) Better metabolic properties. Derivatized chemicals can enhance drug metabolism and lessen reactive or hazardous molecules. (4) Boost security. Deuterated compounds are harmless and have the ability to lessen or eliminate the negative effects of medicinal compounds. (5) Keep things in order. Deuterated chemicals would maintain comparable biological efficacy and hydrogen analogs in earlier research.
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| Animal Protocol |
Female athymic mice (6-8 weeks old) were implanted subcutaneously with human tumor cells (MDA-MB-231, Colo-205, HT-29, DLD-1, NCI-H460, A549). Tumors were allowed to reach 75-150 mg (efficacy studies) or 100-250 mg (mechanistic studies) before treatment. BAY 43-9006 was dissolved in Cremophor EL/ethanol (50:50) at 4× the highest dose (stock prepared fresh every 3 days, stored foil-wrapped at room temperature). Final dosing solutions were prepared daily by diluting stock with water. Lower doses were prepared by diluting 1× solution with Cremophor EL/ethanol/water (12.5:12.5:75). Treatment was administered orally once daily for 9 days (efficacy studies) or 5 days (mechanistic studies). Tumor weight was calculated as length × (width)²/2. Treatments producing >20% lethality or >20% net body weight loss were considered toxic [1].
For immunohistochemistry, tumors were collected 3 hours after final dose, sectioned, and stained. For microvessel detection, paraffin sections were stained with anti-CD31 antibodies (goat polyclonal, 1:750) using Dako Autostainer. Microvessel area and density were quantified using ImagePro Plus software (4 fields/section, 0.644 mm²/field). For pERK detection, sections were stained with anti-pERK1/2 antibody (1:100) using Envision Plus HRP system [1]. |
| References | |
| Additional Infomation |
CM-4307 is being investigated in the clinical trial NCT03602495 (donafenib for 131I-refractory differentiated thyroid cancer). Donafenib is an oral multi-kinase inhibitor that targets Raf kinase and multiple receptor tyrosine kinases (RTKs) with potential antitumor activity. After oral administration, donafenib binds to Raf kinase and blocks its activity, thereby inhibiting the Raf-mediated signal transduction pathway. This can inhibit the proliferation of Raf-expressing tumor cells. Furthermore, the drug may inhibit other unknown RTKs, further inhibiting the proliferation of susceptible tumor cells. Raf is a serine/threonine protein kinase that plays a crucial role in the Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway. Dysregulation of this pathway often leads to tumor cell proliferation and survival.
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| Molecular Formula |
C21H13D3CLF3N4O3
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|---|---|
| Molecular Weight |
467.843
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| Exact Mass |
467.105
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| CAS # |
1130115-44-4
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| Related CAS # |
Sorafenib;284461-73-0;Sorafenib-d4;1207560-07-3;Sorafenib-13C,d3;1210608-86-8
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| PubChem CID |
25191001
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| Appearance |
White to off-white solid powder
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| LogP |
6.086
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
32
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| Complexity |
646
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| Defined Atom Stereocenter Count |
0
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| SMILES |
[2H]C([2H])([2H])NC(=O)C1=NC=CC(=C1)OC2=CC=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F
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| InChi Key |
MLDQJTXFUGDVEO-FIBGUPNXSA-N
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| InChi Code |
InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)/i1D3
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| Chemical Name |
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-(trideuteriomethyl)pyridine-2-carboxamide
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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 |
| 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 : ~100 mg/mL (~213.75 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1375 mL | 10.6874 mL | 21.3748 mL | |
| 5 mM | 0.4275 mL | 2.1375 mL | 4.2750 mL | |
| 10 mM | 0.2137 mL | 1.0687 mL | 2.1375 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05262959 | COMPLETED | Drug: Donafenib, PD-1 Procedure: TACE |
Donafenib | Shanghai Zhongshan Hospital | 2021-12-01 | Phase 2 |
| NCT05205629 | UNKNOWN STATUS | Drug: Donafenib combined with TACE | Donafenib Hepatocellular Carcinoma |
Shanghai Zhongshan Hospital | 2022-01-30 | |
| NCT04402723 | TERMINATED | Drug: Donafenib | Acute Myeloid Leukemia (AML) | Suzhou Zelgen Biopharmaceuticals Co.,Ltd | 2018-11-06 | Phase 1 |
| NCT05161143 | NOT YET RECRUITING | Drug: Donafenib | Hepatocellular Carcinoma | Peking Union Medical College Hospital | 2021-12 | Phase 2 |
| NCT02229071 | COMPLETED | Drug: Donafenib(200mg) Drug: Donafenib(300mg) |
HCC | Suzhou Zelgen Biopharmaceuticals Co.,Ltd | 2014-04 | Phase 1 Phase 2 |
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