918504-65-1 Usage
Description
N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide, also known as Vemurafenib or Zelboraf, is a pyrrolopyridine compound that functions as a potent and selective inhibitor of the BRAFV600E kinase. It is an off-white solid that has been developed as a targeted therapy for patients with metastatic melanoma harboring the BRAFV600E mutation.
Uses
Used in Oncology:
N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide is used as an antitumor agent for the treatment of patients with metastatic melanoma with the BRAFV600E mutation. It works by inhibiting the proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing BRAFV600E or other mutant BRAF proteins altered at codon 600.
Used in Pharmaceutical Industry:
N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide is used as a potent inhibitor of B-RafV600E kinase (IC50=13 nM) compared to its potency against wildtype B-raf (IC50=160 nM). It is fairly selective versus a panel of 200 kinases and has been approved by the United States FDA in August 2011 for the treatment of patients with metastatic melanoma with the BRAFV600E mutation.
Originator
Plexxikon (United States)
Biological Activity
Vemurafenib (PLX4032, RG7204, RO5185426) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM in cell-free assay. 10-fold selective for B-RafV600E over wild-type B-Raf in enzymatic assays and the cellular selectivity can exceed 100-fold. Vemurafenib (PLX4032, RG7204) induces autophagy.
in vitro
PLX4032 inhibits B-RAFV600E, C-RAF, as well as wildtype B-RAF, with IC50 of 31 nM, 48 nM and 100 nM, respectively. PLX4032 also inhibits several non-RAF kinases, including ACK1, KHS1, and SRMS, with IC50 of 18 nM to 51 nM. In melanoma cell lines, the inhibitory effect by PLX4032 depends on B-RAF mutational status, because PLX4032 potently inhibits those harboring B-RAF V600 mutants, including V600E, V600D, V600K, and V600R, but not wildtype or other mutants. The IC50 values of PLX4032 on these cells, including MALME-3M, Colo829, Colo38, A375, SK-MEL28, and A2058, ranges from 20 nM to 1 μM. In these cells, PLX4032 (0.1 μM to 30 μM) also inhibits the phosphorylation of both MEK1/2 and ERK1/2. PLX4032 is highly effective in the treatment of melanoma, for its ability of inhibiting B-RAFV600E. However, PLX4032 displays limited effect in colon cancer patients that also carrying B-RAFV600E oncoprotein. The reason for this is that, in colon cancer cells, B-RAFV600E inhibition by PLX4032 results in a rapid feedback EGFR activation, which compensates for the PLX4032-inhibited cell proliferation.
in vivo
In B-RAFV600E-mutant mice xenograft models, PLX4032 (6 mg/kg–20 mg/kg) inhibits tumor growth. In mice xenograft models of LOX, Colo829, and A375 cells, PLX4032 (12.5 mg/kg–100 mg/kg) inhibits tumor growth and prolongs mice survival.
References
1) Khazak?et al. (2007),?Selective Raf inhibition in cancer therapy; Expert Opin. Ther. Targets,?11?1587
2) Tap?et al.?(2010),?Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma; Neoplasia,?12?637
3) Lee?et al.?(2010),?PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas; Pigment Cell Melanoma Res.,?23?820
4) Flaherty?et al.?(2010),?Inhibition of mutated, activated BRAF in metastatic melanoma; N. Engl. J. Med.,?363?809
Check Digit Verification of cas no
The CAS Registry Mumber 918504-65-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,1,8,5,0 and 4 respectively; the second part has 2 digits, 6 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 918504-65:
(8*9)+(7*1)+(6*8)+(5*5)+(4*0)+(3*4)+(2*6)+(1*5)=181
181 % 10 = 1
So 918504-65-1 is a valid CAS Registry Number.
918504-65-1Relevant articles and documents
Simple preparation method of vemurafenib and analogues thereof
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, (2019/10/02)
The invention provides a simple preparation method of vemurafenib and analogues thereof. The method includes: subjecting para-substituted phenylacetaldehyde II and N-[2, 4-disubstituted-3-(cyanopropionyl)phenyl]n-propanesulfonamide III to azeotropic dewatering and condensation reaction under alkaili catalysis, condensing the obtained condensation product and the methylenation reagent V(N, N-dimethylformamide or tri-orthoformate), and then performing cyclization with ammonia to obtain vemurafenib or analogues thereof. The method for preparation of vemurafenib provided by the invention has the characteristics of low cost, mild process conditions, low operation requirements, short reaction time, high production efficiency, simple process operation, little waste water production, green and environmental protection, high yield and purity, and is beneficial to green industrial production of vemurafenib. At the same time, the method provided by the invention can prepare vemurafenib analogues,and is of important significance for the drug efficacy study of similar compounds.
SUBSTANTIALLY PURE VEMURAFENIB AND ITS SALTS
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Paragraph 0126-0127, (2018/12/04)
The present invention relates to a process for the preparation substantially pure propane-1-sulfonicacid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide or Vemurafenib of Formula (I). The present invention further relates to a process for the preparation substantially pure propane-1-sulfonic acid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3 -b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide trifluoro methane sulfonic acid salt or Vemurafenib triflate of Formula (VII)
NOVEL PROCESSES FOR THE PREPARATION OF VEMURAFENIB
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, (2015/06/08)
The present invention provides novel intermediates of vemurafenib or a pharmaceutically acceptable salt thereof and processes for its preparation. The present invention also provides novel processes for preparation of vemurafenib or a pharmaceutically acceptable salt thereof using the novel intermediates.
