Donafenib (Sorafenib D3)

Catalog No.S9621 Synonyms: Bay 43-9006 D3, CM-4307

For research use only.

Donafenib (Sorafenib D3, Bay 43-9006 D3, CM-4307) is the deuterium labeled Sorafenib. Sorafenib is a multikinase inhibitor IC50s of 6 nM, 15 nM, 20 nM and 22 nM for Raf-1, mVEGFR-2, mVEGFR-3 and B-RAF, respectively.

Donafenib (Sorafenib D3) Chemical Structure

CAS No. 1130115-44-4

Purity & Quality Control

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Biological Activity

Description Donafenib (Sorafenib D3, Bay 43-9006 D3, CM-4307) is the deuterium labeled Sorafenib. Sorafenib is a multikinase inhibitor IC50s of 6 nM, 15 nM, 20 nM and 22 nM for Raf-1, mVEGFR-2, mVEGFR-3 and B-RAF, respectively.
Targets
Raf-1 [1]
(Cell-free assay)
mVEGFR-2 [1]
(Cell-free assay)
mVEGFR-3 [1]
(Cell-free assay)
B-Raf [1]
(Cell-free assay)
6 nM 15 nM 20 nM 22 nM
In vitro

BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrates significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor β, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrates inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non–small-cell lung cancer cell lines expressing mutant KRAS are insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor β, and VEGFR-3 cellular receptor autophosphorylation is also observed for BAY 43-9006.[1]

In vivo

Once daily oral dosing of BAY 43-9006 demonstrates broad-spectrum antitumor activity in colon, breast, and non–small-cell lung cancer xenograft models. Immunohistochemistry demonstrates a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrates significant inhibition of neovascularization in all three of the xenograft models.[1]

Protocol (from reference)

Cell Research:

[1]

  • Cell lines: MDA-MB-231, Colo-205, HT-29, DLD-1, NCI-H460, A549 cell lines
  • Concentrations: 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM
  • Incubation Time: 120 min
  • Method:

    Tumor cell lines are plated at 2 × 105 cells per well in 12-well tissue culture plates in DMEM growth media (10% heat-inactivated FCS) overnight. Cells are washed once with serum-free media and incubated in DMEM supplemented with 0.1% fatty acid-free BSA containing various concentrations of Donafenib (Sorafenib D3, BAY 43-9006) in 0.1% DMSO for 120 minutes to measure changes in basal pMEK 1/2, pERK 1/2, or pPKB. Cells are washed with cold PBS (PBS containing 0.1 mmol/L vanadate) and lysed in a 1% (v/v) Triton X-100 solution containing protease inhibitors. Lysates are clarified by centrifugation, subjected to SDS-PAGE, transferred to nitrocellulose membranes, blocked in TBS-BSA, and probed with anti-pMEK 1/2 (Ser217/Ser221; 1:1000), anti-MEK 1/2, anti-pERK 1/2 (Thr202/Tyr204; 1:1000), anti-ERK 1/2, anti-pPKB (Ser473; 1:1000), or anti-PKB primary antibodies. Blots are developed with horseradish peroxidase (HRP)-conjugated secondary antibodies and developed with Amersham ECL reagent on Amersham Hyperfilm.

Animal Research:

[1]

  • Animal Models: Female NCr-nu/nu mice
  • Dosages: 7.5 mg/kg, 15 mg/kg, 30 mg/kg, 60 mg/kg
  • Administration: Oral gavage

Solubility (25°C)

In vitro

Chemical Information

Molecular Weight 467.84
Formula

C21H13D3ClF3N4O3

CAS No. 1130115-44-4
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CNC(=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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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04612712 Recruiting Drug: Donafenib Tosilate Tablets|Biological: KN046 Injection Advanced Gastrointestinal Tumors Suzhou Zelgen Biopharmaceuticals Co.Ltd|Jiangsu Alphamab Biopharmaceuticals Co. Ltd January 19 2021 Phase 1|Phase 2
NCT04816123 Completed Drug: [14C]Donafenib Healthy Male Adult Suzhou Zelgen Biopharmaceuticals Co.Ltd October 9 2018 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-08-01)

Tech Support

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

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