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PLX4032

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PLX4032 Basic information

Product Name:
PLX4032
Synonyms:
  • N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide
  • PLX4032 (VeMurafenib)
  • PLX4032, RG7204, ZELBORAF, RO5185426
  • R7204
  • N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaM
  • PLX4032, R7204, RG7204, RO5185426
  • VeMurafenib (PLX4032, RG7204)
  • N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide Vemurafenib PLX 4032
CAS:
918504-65-1
MF:
C23H18ClF2N3O3S
MW:
489.92
Product Categories:
  • API
  • Heterocycles
  • Intermediates & Fine Chemicals
  • Pharmaceuticals
  • Protein Kinase Inhibitors and Activators
  • Sulfur & Selenium Compounds
  • Aromatics
  • Inhibitor
  • RG7204
  • Antineoplastic
  • Inhibitors
  • MAPK
Mol File:
918504-65-1.mol
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PLX4032 Chemical Properties

Density 
1.46
storage temp. 
-20°C
solubility 
Soluble in DMSO (up to 100 mg/ml)
form 
White powder.
pka
6.26±0.10(Predicted)
color 
White or off-white
Stability:
Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
CAS DataBase Reference
918504-65-1
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Safety Information

HS Code 
29339900
Hazardous Substances Data
918504-65-1(Hazardous Substances Data)
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PLX4032 Usage And Synthesis

Description

In August 2011, the United States FDA approved vemurafenib (PLX- 4032, RO-5185426) for the treatment of patients with metastatic melanoma with the BRAFV600E mutation. Vemurafenib has been developed as a targeted therapy for patients with the BRAF gene mutation since oncogenic B-raf signaling is implicated in approximately 50% of melanomas. Vemurafenib was identified based on an initial high-throughput screen followed by the extensive use of structure-based drug design. Vemurafenib is a potent inhibitor of B-RafV600E kinase (IC50=13 nM) compared to its potency against wildtype B-raf (IC50=160 nM) and is fairly selective versus a panel of 200 kinases. It does inhibit other kinases (RAF1, SRMS, ACK1, MAP4K5, and FGR) and mutant B-raf kinases (BRAFV600K, BRAFV600D, and BRAFV600R) with enzyme IC50's of <100 nM.

Chemical Properties

Off-White Solid

Originator

Plexxikon (United States)

Uses

Vemurafenib selective BRAFV600E kinase inhibitor; an antitumor agent. Vemurafenib functions 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.

Uses

Vemurafenib (PLX4032, RG7204) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM

Uses

PLX4032 is an orally bioavailable, ATP-competitive inhibitor of mutant V600E and wild type B-Raf kinases (IC50s = 31 and 100 nM, respectively). It inhibits cell proliferation in a variety of cell lines expressing B-Raf V600E and synergizes strongly with taxol, vinblastine, and oxaliplatin in inhibiting the proliferation of B-RafV600E transformed cancer cells. PLX4032 is effective against the growth of tumors bearing the B-Raf V600E mutation.[Cayman Chemical]

Definition

ChEBI: A pyrrolopyridine that is 1H-pyrrolo[2,3-b]pyridine which is substituted at position 5 by a p-chlorophenyl group and at positions 3 by a 3-amino-2,6-difluorobenzoyl group, the amino group of which has undergone ormal condensation with propane-1-sulfonic acid to give the corresponding sulfonamide. An inhibitor of BRAF and other kinases.

brand name

Zelboraf

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

PLX4032Supplier

AdooQ Bioscience CHINA Gold
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