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918505-84-7 molecular structure
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N-(3-{5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide

ChemBase ID: 4652
Molecular Formular: C17H14ClF2N3O3S
Molecular Mass: 413.8261664
Monoisotopic Mass: 413.04124644
SMILES and InChIs

SMILES:
O=S(=O)(CCC)Nc1c(F)c(c(cc1)F)C(=O)c1c[nH]c2c1cc(cn2)Cl
Canonical SMILES:
CCCS(=O)(=O)Nc1ccc(c(c1F)C(=O)c1c[nH]c2c1cc(Cl)cn2)F
InChI:
InChI=1S/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)
InChIKey:
YZDJQTHVDDOVHR-UHFFFAOYSA-N

Cite this record

CBID:4652 http://www.chembase.cn/molecule-4652.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
N-(3-{5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide
IUPAC Traditional name
N-(3-{5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide
Synonyms
N-{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl}propane-1-sulfonamide
PLX-4720
N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide
CAS Number
918505-84-7
PubChem SID
160968084
99443470
PubChem CID
24180719

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem ALOGPS 2.1
Acid pKa 7.1725125  H Acceptors
H Donor LogD (pH = 5.5) 2.9671185 
LogD (pH = 7.4) 2.622226  Log P 2.9752579 
Molar Refractivity 96.8329 cm3 Polarizability 37.8464 Å3
Polar Surface Area 91.92 Å2 Rotatable Bonds
Lipinski's Rule of Five true 
Log P 3.59  LOG S -4.99 
Solubility (Water) 4.22e-03 g/l 

PROPERTIES

PROPERTIES

Physical Property Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Solubility
DMSO expand Show data source
Storage Condition
-20°C expand Show data source
MSDS Link
Download expand Show data source
Target
B-Raf expand Show data source
Salt Data
Free Base expand Show data source
Certificate of Analysis
Download expand Show data source

DETAILS

DETAILS

DrugBank DrugBank Selleck Chemicals Selleck Chemicals TRC TRC
DrugBank - DB06999 external link
Drug information: experimental
Selleck Chemicals - S1152 external link
Biological Activity
Description PLX-4720 is a potent and selective inhibitor of B-RafV600E and c-Raf-1Y340D/Y341D with IC50 of 13 nM and 6.7 nM, respectively.
Targets B-RafV600E c-Raf-1Y340D/Y341D
IC50 13 nM 6.7 nM [1]
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. [1] 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. [2]
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. [1] PLX-4720 treatment at 30 mg/kg/day significant inhibits the tumor growth of 8505c xenografts by >90%, and dramatically decreases distant lung metastases. [3]
Clinical Trials
Features
Protocol
Kinase Assay [1]
In vitro Raf kinase activities The in vitro kinase activities of wild type Raf and mutants are determined by measuring phosphorylation of biotinylated-MEK protein using Perkin-Elmer's AlphaScreen Technology. For each enzyme (0.1 ng), 20-μL reactions are carried out in 20 mM Hepes (pH 7.0), 10 mM MgCl2, 1 mM DTT, 0.01% Tween-20, 100 nM biotin-MEK protein, various ATP concentrations, and increasing concentrations of PLX-4720 at room temperature. Reactions are stopped at 2, 5, 8, 10, 20, and 30 minutes with 5 μL of a solution containing 20 mM Hepes (pH 7.0), 200 mM NaCl, 80 mM EDTA, and 0.3% BSA. The stop solution also includes phospho-MEK Antibody, Streptavidin-coated Donor beads and Protein A Acceptor beads from the AlphaScreen Protein A Detection Kit. The antibody and beads are preincubated in stop solution in the dark at room temperature for 30 minutes. The final dilution of antibody is 1/2,000, and the final concentration of each bead is 10 μg/mL. The assay plates are incubated at room temperature for one hour then are read on a PerkinElmer AlphaQuest reader.
Cell Assay [1]
Cell Lines COLO205, A375, WM2664, COLO829, HT716, SW620, H460, Calu-6, HCT116, SK-MEL2, SK-MEL3, Lovo, H1299, 1205Lu, and C8161 cells
Concentrations Dissolved in DMSO, final concentrations ~1 mM
Incubation Time 24, 48, and 72 hours
Methods Cells are treated with various concentrations PLX-4720 for 24, 48, and 72 hours. Cell proliferation is measured by using the CellTiter-Glo Luminescent Cell Viability Assay or MTT assay. For cell cycle analysis, supernatant and cells are collected, pelleted, and fixed with 70% ethanol. Before staining with propidium iodide (10 μg/mL), cells are incubated for 1 hour at 37 °C in 0.5 mg/mL RNase I to rid samples of residual RNA contamination. Samples are then analyzed by using the EPICS XL apparatus. For the assessment of apoptosis, media and cells are harvested and pelleted before staining with annexin-FITC and propidium iodide. Samples are subsequently analyzed by using the EPICS XL apparatus.
Animal Study [1]
Animal Models Female athymic mice (NCr nu/nu) implanted s.c. with COLO205 cells, and SCID mice with 1205Lu or C8161 cells
Formulation Suspended in vehicle (5% DMSO, 1% methylcellulose)
Doses 5, 20, or 100 mg/kg
Administration Oral gavage once or twice daily
References
[1] Tsai J, et al. Proc Natl Acad Sci U S A, 2008, 105(8), 3041-3046.
[2] Paraiso KH, et al. Cancer Res, 2011, 71(7), 2750-2760.
[3] Nucera C, et al. Proc Natl Acad Sci U S A, 2010, 107(23), 10649-10654.
Toronto Research Chemicals - P635000 external link
PLX4720 is a selective inhibitor of mutant B-RAF and its analog, PLX4032, is currently undergoing clinical trials in melanoma. An antitumor agent.

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