| Identification | Back Directory | [Name]
RAF265(CHIR-265) | [CAS]
927880-90-8 | [Synonyms]
RAF265
CS-1852
RAF265, >=98%
RAF265(CHIR-265)
CHIR-265 or RAF265
RAF265 or CHIR-265
CHIR265;RAF-265;CHIR 265;
RAF265(CHIR-265) USP/EP/BP
RAF265 (CHIR-265);RAF-265; CHIR265
1-Methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]-oxy]-N-[4-(trifluoromethyl)
1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine
1-Methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine
1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine
1H-Benzimidazol-2-amine, 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-
RAF 265 1-Methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine
1-Methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine RAF265 (CHIR-265) | [Molecular Formula]
C24H16F6N6O | [MDL Number]
MFCD16659061 | [MOL File]
927880-90-8.mol | [Molecular Weight]
518.41 |
| Questions And Answer | Back Directory | [Description]
RAF265, also known as (CHIR-265), is an arylaminobenzimidazole-based B-RAF, C-RAF, and VEGFR2 inhibitor developed by Chiron Corporation, later acquired by Novartis. | [Biological Activity]
RAF265 is a novel, orally active, small molecule with potent inhibitory activity against B-Raf kinase and additional antiangiogenic activity through inhibition of vascular endothelial growth factor receptor type 2 (VEGFR-2) in non-clinical studies. |
| Chemical Properties | Back Directory | [Boiling point ]
667.6±65.0 °C(Predicted) | [density ]
1.50 | [storage temp. ]
Store at -20°C | [solubility ]
≥25.9 mg/mL in DMSO; insoluble in H2O; ≥7.97 mg/mL in EtOH with ultrasonic | [form ]
Solid | [pka]
9.07±0.27(Predicted) | [color ]
White to khaki | [Sensitive ]
Light Sensitive |
| Hazard Information | Back Directory | [Uses]
RAF 265 is a multikinase inhibitor that has displayed BRAF inhibiting activity in clinical trials. It could be used in the treatment of a subpopulation of human melanoma tumors. Has cytotoxic effect o
f on MDA-MB-231 cells. RAF265 when used with BEZ-235 inhibited ERK, PI3K signaling that reduced growth, proliferation and development of drug resistance in human thyroid cancer cells. | [Uses]
RAF265 (CHIR-265) is an oral, highly selective RAF and VEGFR kinase inhibitor with IC50 of of 5 to 10 μM. | [Definition]
ChEBI: 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine is an aromatic ether. | [Synthesis]
Example 69: Preparation of 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine
1. 4-(Trifluoromethyl)phenyl isothiocyanate (200 mg, 1 mmol) was added to a solution of N1-methyl-4-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-1,2-benzenediamine (350 mg, 1 mmol) in 3 mL of acetonitrile.
2. The reaction mixture was stirred at room temperature for 20 min and the reaction progress was monitored by HPLC.
3. Triethylamine (0.3 mL, 2.2 mmol) was added to the reaction system followed by 2-chloro-1-methylpyridinium iodide (270 mg, 1.05 mmol).
4. The reaction mixture was heated to 50 °C and maintained at this temperature for 5 hours.
5. Upon completion of the reaction, the heating was stopped and 1.5 mL of water was added.
6. The mixture was continued to be stirred for 2 hours, after which the solid product was collected by filtration.
7. The solid was washed with acetonitrile/water (2:1, v/v, 3 x 1 mL) to give a final 317 mg (61% yield) of the target compound 1 -methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine. | [in vivo]
In single-compound efficacy studies, optimal dosing of RAD001 and RAF265 is 5 to 12 mg/kg daily and 30 mg/kg every two days, respectively. However, combination tolerability studies in nontumor-bearing mice defin dose-limiting toxicity as a 10% weight loss with the combination of RAD001 at a dose of 12 mg/kg daily and RAF265 at a dose of 20 mg/kg every two days. Therefore, the combination of RAF265 at a dose of 12 mg/kg qd and RAD001 at a dose of 12 mg/kg qd seems to be the maximal tolerated dose. RAD001 and RAF265 are both given at a dose of 12 mg/kg qd, alone or concurrently, over 6 days. After a 2-day stop, the compounds are given for another 6 days, and the treatment is then stopped. To confirm the potential of the combination of RAF265 and RAD001, the antitumor effect of the combination is tested in HCT116 xenografts (KRAS mut, PIK3CA mut). In HCT116 xenografts, RAD001 or RAF265 given alone shows 60% to 65% and 71% to 72% TVI%, respectively[1]. | [target]
B-Raf | [IC 50]
VEGFR2; RAF | [References]
[1]huang t1, karsy m, zhuge j, zhong m, liu d. b-raf and the inhibitors: from bench to bedside. j hematol oncol. 2013 apr 25;6:30. doi: 10.1186/1756-8722-6-30.
[2]garcia-gomez a1, ocio em, pandiella a, san miguel jf, garayoa m. raf265, a dual braf and vegfr2 inhibitor, prevents osteoclast formation and resorption. therapeutic implications. invest new drugs. 2013 feb;31(1):200-5. doi: 10.1007/s10637-012-9845-3. epub 2012 jul 7.
[3]su y1, vilgelm ae, kelley mc, hawkins oe, liu y, boyd kl, kantrow s, splittgerber rc, short sp, sobolik t, zaja-milatovic s, dahlman kb, amiri ki, jiang a, lu p, shyr y, stuart dd, levy s, sosman ja, richmond a. raf265 inhibits the growth of advanced human melanoma tumors. clin cancer res. 2012 apr 15;18(8):2184-98. doi: 10.1158/1078-0432.ccr-11-1122. epub 2012 feb 20. |
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