918505-84-7 Usage
Description
N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide, also known as PLX4720, is a potent and selective inhibitor of the Raf kinase B-Raf(V600E). It is an orally-available, ATP-competitive, azaindole-based inhibitor with an IC50 value of 13 nM. PLX4720 has additional activity towards mutant forms of c-Raf-1 (Y340D, Y341D) at an IC50 of 6.7 nM, with modest single micromolar activity versus kinases such as FRK, CSK, SRC, FGFR, KDR, HGK, and Aurora A. It is a derivative of vemurafenib, with the p-chlorophenyl group replaced by chlorine.
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/
Check Digit Verification of cas no
The CAS Registry Mumber 918505-84-7 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 5 respectively; the second part has 2 digits, 8 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 918505-84:
(8*9)+(7*1)+(6*8)+(5*5)+(4*0)+(3*5)+(2*8)+(1*4)=187
187 % 10 = 7
So 918505-84-7 is a valid CAS Registry Number.
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)
918505-84-7Relevant articles and documents
Rapid, microwave-assisted organic synthesis of selective V600EBRAF inhibitors for preclinical cancer research
Buck, Jason R.,Saleh, Sam,Imam Uddin, Md.,Manning, H. Charles
, p. 4161 - 4165 (2012/08/29)
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.
