B1407-100mg | Dabrafenib (GSK2118436) [1195765-45-7] Clinisciences

Background

Dabrafenib is a specific inhibitor of BRAF V600 mutants with IC50 values of 0.5nM, 0.6nM and 1.9nM against V600E, V600K and V600D, respectively [1].

BRAF plays a central role in regulating MAPK signaling pathway which regulates cell growth, division and differentiation. The V600E mutation of BRAF increases the kinase activity and is involved in metastatic melanomas. Dabrafenib is an ATP-competitive and reversible inhibitor of BRAF mutants. It potently inhibits BRAFV600E, BRAFV600K and BRAFV600D with IC50 values of 0.5nM, 0.6nM and 1.9nM, respectively. Dabrafenib is currently approved by FDA and is widely used in cancer patients harboring BRAF mutations. It is reported that treatment of dabrafenib shrinks the overall size of brain metastases in patients. It also has an impressive 60% response rate for melanomas outside of the brain. Dabrafenib provides a significant survival benefit in patients with metastatic melanoma [1, 2].

References:
[1] Hong S, Hong S. Overcoming metastatic melanoma with BRAF inhibitors. Archives of pharmacal research, 2011, 34(5): 699-701.
[2] Hong D S, Vence L, Falchook G, et al. BRAF (V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clinical Cancer Research, 2012, 18(8): 2326-2335.

Product Citation

1. Shelby Giza, Jorge A Mojica-Santiago, et al. "Microphysiological system for studying contractile differences in young, active, and old, sedentary adult derived skeletal muscle cells." Aging Cell. 2022 Jul;21(7):e13650. PMID: 35653714
2. Yina Liao, Yao Gao, et al. "Melatonin synergizes BRAF-targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling." J Cell Mol Med. 2020 Sep 15. PMID: 32935463
3. Cheriyan VT, Alsaab H, et al. "A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers." Oncotarget. 2018 Jul 3;9(51):29680-29697. PMID: 30038713
4. Azimi A, Caramuta S, et al. "Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors." Mol Syst Biol. 2018 Mar 5;14(3):e7858. PMID: 29507054
5. Sieber J, Wieder N, et al. "GDC-0879, a BRAF(V600E) Inhibitor, Protects Kidney Podocytes from Death." Cell Chem Biol. 2017 Dec 6. PMID: 29249695

Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	519.56
Cas No.	1195765-45-7
Formula	C23H20F3N5O2S2
Solubility	≥26 mg/mL in DMSO; insoluble in H2O; ≥2.59 mg/mL in EtOH with gentle warming and ultrasonic
Chemical Name	N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
SDF	Download SDF
Canonical SMILES	CC(C)(C)C1=NC(=C(S1)C2=NC(=NC=C2)N)C3=C(C(=CC=C3)NS(=O)(=O)C4=C(C=CC=C4F)F)F
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment [1, 2]:
Cell lines	B-RafV600E-driven melanoma lines, SKMEL28 and A375P F11, and colorectal carcinoma cells Colo205, HT29 cells
Preparation method	The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
Reacting condition	10 μM for 24 h
Applications	Dabrafenib effectively inhibited cell proliferation of B-RafV600E-driven melanoma lines, SKMEL28 and A375P F11 (IC50 = 3 and 8 nM, respectively), and colorectal carcinoma cells Colo205 (IC50 = 7 nM). Moreover, dabrafenib selectively inhibited RIP3 and inhibited RIP3-mediated necroptosis for HT29 cells.
Animal experiment [1, 2]:
Animal models	CD1 nu/nu mice bearing A375P F11 (B-RafV600E) tumors model
Dosage form	0.1, 1, 10, and 100 mg/kg, oral administration, once daily for 14 days or 300 mg/kg, 100 mg/kg dabrafenib (p.o.).
Applications	Dabrafenib dose-dependently inhibited tumor growth and reduced pERK levels in A375P F11 (B-RafV600E) human melanoma tissue in vivo. Additionally, dabrafenib alleviated acetaminophen-induced liver injury in mice.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: 1. Rheault, T. R., Stellwagen, J. C., Adjabeng, G. M., Hornberger, K. R., Petrov, K. G., Waterson, A. G., Dickerson, S. H., Mook, R. A., Jr., Laquerre, S. G., King, A. J., Rossanese, O. W., Arnone, M. R., Smitheman, K. N., Kane-Carson, L. S., Han, C., Moorthy, G. S., Moss, K. G. and Uehling, D. E. (2013) Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors. ACS Med Chem Lett. 4, 358-362 2. Li, J. X., Feng, J. M., Wang, Y., Li, X. H., Chen, X. X., Su, Y., Shen, Y. Y., Chen, Y., Xiong, B., Yang, C. H., Ding, J. and Miao, Z. H. (2014) The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury. Cell Death Dis. 5, e1278

Biological Activity

Description	Dabrafenib (GSK2118436) is a inhibitor of mutant BRAFV600 specific with an IC50 value of 0.8 nM.
Targets	B-Raf (V600E)	B-Raf	C-Raf
IC50	0.8 nM	3.2 nM	5.0 nM

Quality Control

Purity = 98.36%

Chemical structure

Dabrafenib (GSK2118436) [1195765-45-7]

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Background

Product Citation

Chemical Properties

Protocol

Biological Activity

Quality Control

Chemical structure

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