918505-84-7

Basic information

• Product Name: N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide
• Synonyms: 1-PropanesulfonaMide, N-[3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-;N-[3-[(5-Chloro-1H-pyrrol...;N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide PLX 4720;PLX 4720 N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide;PLX4720, >=98%;Raf Kinase Inhibitor V;PLX-4720, N-(3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide;N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide
• CAS NO: 918505-84-7
• Molecular Formula: C17H14ClF2N3O3S
• Molecular Weight: 413.831
• Product Categories: Intermediates & Fine Chemicals;Isotope Labelled Compounds;Pharmaceuticals;Sulfur & Selenium Compounds;Inhibitors;MAPK;Aromatics;Heterocycles
• Mol File: 918505-84-7.mol

Chemical Properties

• Appearance: /
• Density: 1.55
• Refractive Index: 1.645
• Storage Temp.: +2C to +8C
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated)
• PKA: 6.20±0.10(Predicted)
• CAS DataBase Reference: N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide(CAS DataBase Reference)
• NIST Chemistry Reference: N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide(918505-84-7)
• EPA Substance Registry System: N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide(918505-84-7)

Safety Data

• Hazardous Substances Data: 918505-84-7(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
PLX4720 is used as a selective inhibitor of mutant B-RAF for the treatment of melanoma and thyroid cancer. It preferentially inhibits ERK phosphorylation in tumor cell lines bearing the V600E allele, inducing cell cycle arrest and apoptosis exclusively in B-Raf (V600E)-positive cells. In melanoma models, it has shown preclinical activity, and in an orthotopic 8505c human thyroid cancer mice model, it caused a significant reduction in tumor growth (>90%) and dramatically decreased lung metastases.
Used in Clinical Trials:
The analog of PLX4720, PLX4032, is currently undergoing clinical trials for the treatment of melanoma, further validating the potential therapeutic applications of this compound in oncology.

Biological activity

PLX4720 is a potent and selective inhibitor of B-RafV600E with IC50 of 13 nM in a cell-free assay, equally potent to c-Raf-1(Y340D and Y341D mutations), 10-fold selectivity for B-RafV600E than wild-type B-Raf.

In vitro

PLX-4720 displays >10 times selectivity against wild type B-Raf, and >100 times selectivity over other kinases such as Frk, Src, Fak, FGFR, and Aurora A with IC50 of 1.3-3.4 μM. PLX-4720 significantly inhibits the ERK phosphorylation in cell lines bearing B-RafV600E with IC50 of 14-46 nM, but not the cells with wild-type B-Raf. PLX-4720 significantly inhibits the growth of tumor cell lines bearing the B-RafV600E oncogene, such as COLO205, A375, WM2664, and COLO829 with GI50 of 0.31 μM, 0.50 μM, 1.5 μM, and 1.7 μM, respectively. In addition, PLX-4720 treatment at 1 μM induces cell cycle arrest and apoptosis exclusively in the B-RafV600E-positive 1205Lu cells, but not in the B-Raf wild-type C8161 cells. PLX-4720 treatment (10 μM) significantly induces >14-fold expression of BIM in the PTEN+ cells, compared with the PTEN-cell lines (4-fold), giving an explanation of the resistance of PTEN-cells to PLX-4720-induced apoptosis.

In vivo

Oral administration of PLX-4720 at 20 mg/kg/day induces significant tumor growth delays and regressions in B-RafV600E-dependent COLO205 tumor xenografts, without obvious adverse effects in mice even at dose of 1 g/kg. PLX-4720 at 100 mg/kg twice daily almost completely eliminates the 1205Lu xenografts bearing B-RafV600E, while has no activity against C8161 xenografts bearing wild-type B-Raf. The anti-tumor effects of PLX-4720 correlate with the blockade of MAPK pathway in those cells harboring the V600E mutation. PLX-4720 treatment at 30 mg/kg/day significant inhibits the tumor growth of 8505c xenografts by >90%, and dramatically decreases distant lung metastases.

References

http://www.cellagentech.com/PLX-4720/

InChI:InChI=1/C17H14ClF2N3O3S/c1-2-5-27(25,26)23-13-4-3-12(19)14(15(13)20)16(24)11-8-22-17-10(11)6-9(18)7-21-17/h3-4,6-8,23H,2,5H2,1H3,(H,21,22)

Upstream product

• 367-25-9 2,4-difluorophenylamine 
• 918523-57-6 N-(3,5-difluorophenyl)propane-1-sulfonamide 
• 1021854-28-3 N-(3-((5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)(hydroxyl)methyl)2,4-difluorophenyl)propane-1-sulfonamide 

Relevant articles and documents

Rapid, microwave-assisted organic synthesis of selective V600EBRAF inhibitors for preclinical cancer research

We report dramatically improved total syntheses of two highly selective V600EBRAF inhibitors, PLX4720 and PLX4032, that leverages microwave-assisted organic synthesis (MAOS). Compared with previously reported approaches, our novel MAOS method significantly reduces overall reaction time without compromising yield. In addition to providing a gram-scale route to these compounds for preclinical oncology research, we anticipate this approach could accelerate the synthesis of azaindoles in high-throughput, library-based formats.

PYRROLO[2,3-B] PYRIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS

Compounds of formula III which are active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.