PLX4032 CAS 918504-65-1

Introduction：Basic information about PLX4032 CAS 918504-65-1, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

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-propanesulfonamideVemurafenib 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

PLX4032 Chemical Properties

• density: 1.46
• storage temp.: -20°C
• solubility: Soluble in DMSO (up to 100 mg/ml)
• pka: 6.26±0.10(Predicted)
• form: White powder.
• 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.
• InChIKey: GPXBXXGIAQBQNI-UHFFFAOYSA-N
• SMILES: C(S(NC1=CC=C(F)C(C(C2C3=CC(C4=CC=C(Cl)C=C4)=CN=C3NC=2)=O)=C1F)(=O)=O)CC
• CAS DataBase Reference: 918504-65-1

Safety Information

• HS Code: 29339900
• Hazardous Substances Data: 918504-65-1(Hazardous Substances Data)

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 melanomawith the BRAFV600E mutation. Vemurafenib has been developed as atargeted therapy for patients with the BRAF gene mutation since oncogenicB-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 200kinases. It does inhibit other kinases (RAF1, SRMS, ACK1,MAP4K5, and FGR) and mutant B-raf kinases (BRAFV600K,BRAFV600D, and BRAFV600R) with enzyme IC_50'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.

target

B-RafV600E

storage

Store at -20°C

References

[1] VLADIMIR KHAZAK. Selective Raf inhibition in cancer therapy.[J]. Expert Opinion on Therapeutic Targets, 2007, 11 12: 1587-1609. DOI:10.1517/14728222.11.12.1587
[2] WILLIAM D. TAP . Pharmacodynamic Characterization of the Efficacy Signals Due to Selective BRAF Inhibition with PLX4032 in Malignant Melanoma[J]. Neoplasia, 2010, 12 8: Pages 637-649, IN3. DOI:10.1593/neo.10414
[3] JOHN T. LEE. PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas[J]. Pigment Cell & Melanoma Research, 2010, 23 6: 820-827. DOI:10.1111/j.1755-148x.2010.00763.x
[4] KEITH T FLAHERTY. Inhibition of mutated, activated BRAF in metastatic melanoma.[J]. New England Journal of Medicine, 2010, 363 9: 809-819. DOI:10.1056/nejmoa1002011