PLX4720
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MedKoo CAT#: 202272

CAS#: 918505-84-7

Description: PLX4720 is a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele.

Chemical Structure

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PLX4720
CAS# 918505-84-7
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 202272
Name: PLX4720
CAS#: 918505-84-7
Chemical Formula: C17H14ClF2N3O3S
Exact Mass: 413.04
Molecular Weight: 413.820
Elemental Analysis: C, 49.34; H, 3.41; Cl, 8.57; F, 9.18; N, 10.15; O, 11.60; S, 7.75

Price and Availability

Size Price Availability Quantity
50mg USD 150 Ready to ship
100mg USD 250 Ready to ship
200mg USD 450 Ready to ship
500mg USD 950 Ready to ship
1g USD 1650 Ready to ship
2g USD 2950 Ready to ship
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Synonym: PLX 4720; PLX4720; PLX-4720.

IUPAC/Chemical Name: N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

InChi Key: YZDJQTHVDDOVHR-UHFFFAOYSA-N

InChi Code: 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)

SMILES Code: CCCS(=O)(NC1=CC=C(F)C(C(C2=CNC3=NC=C(Cl)C=C32)=O)=C1F)=O

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >3 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info: PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven tumors. see http://www.ncbi.nlm.nih.gov/pubmed/18287029.    

Biological target: PLX-4720 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), and 10-fold selectivity for B-RafV600E than wild-type B-Raf.
In vitro activity: 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. Reference: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18287029/
In vivo activity: 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. Reference: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18287029/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 72.50

Preparing Stock Solutions

The following data is based on the product molecular weight 413.82 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol: 1. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6. doi: 10.1073/pnas.0711741105. Epub 2008 Feb 19. PMID: 18287029; PMCID: PMC2268581. 2. Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, Wood E, Fedorenko IV, Sondak VK, Anderson AR, Ribas A, Palma MD, Nathanson KL, Koomen JM, Messina JL, Smalley KS. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011 Apr 1;71(7):2750-60. doi: 10.1158/0008-5472.CAN-10-2954. Epub 2011 Feb 11. PMID: 21317224; PMCID: PMC3070772.
In vivo protocol: 1. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6. doi: 10.1073/pnas.0711741105. Epub 2008 Feb 19. PMID: 18287029; PMCID: PMC2268581. 2. Nucera C, Porrello A, Antonello ZA, Mekel M, Nehs MA, Giordano TJ, Gerald D, Benjamin LE, Priolo C, Puxeddu E, Finn S, Jarzab B, Hodin RA, Pontecorvi A, Nose V, Lawler J, Parangi S. B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression. Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10649-54. doi: 10.1073/pnas.1004934107. Epub 2010 May 24. PMID: 20498063; PMCID: PMC2890809.

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1: Kamata T, Dankort D, Kang J, Giblett S, Pritchard CA, McMahon M, Leavitt AD. Hematopoietic expression of oncogenic BRAF promotes aberrant growth of monocyte-lineage cells resistant to PLX4720. Mol Cancer Res. 2013 Dec;11(12):1530-41. doi: 10.1158/1541-7786.MCR-13-0294. Epub 2013 Oct 23. PubMed PMID: 24152792; PubMed Central PMCID: PMC3869667.

2: Eum KH, Ahn SK, Kang H, Lee M. Differential inhibitory effects of two Raf-targeting drugs, sorafenib and PLX4720, on the growth of multidrug-resistant cells. Mol Cell Biochem. 2013 Jan;372(1-2):65-74. doi: 10.1007/s11010-012-1446-0. Epub 2012 Sep 2. PubMed PMID: 22941213.

3: Shao Y, Aplin AE. BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma. Cell Death Differ. 2012 Dec;19(12):2029-39. doi: 10.1038/cdd.2012.94. Epub 2012 Aug 3. PubMed PMID: 22858545; PubMed Central PMCID: PMC3504716.

4: Oikonomou E, Koc M, Sourkova V, Andera L, Pintzas A. Selective BRAFV600E inhibitor PLX4720, requires TRAIL assistance to overcome oncogenic PIK3CA resistance. PLoS One. 2011;6(6):e21632. doi: 10.1371/journal.pone.0021632. Epub 2011 Jun 27. PubMed PMID: 21738740; PubMed Central PMCID: PMC3124547.

5: Nucera C, Nehs MA, Nagarkatti SS, Sadow PM, Mekel M, Fischer AH, Lin PS, Bollag GE, Lawler J, Hodin RA, Parangi S. Targeting BRAFV600E with PLX4720 displays potent antimigratory and anti-invasive activity in preclinical models of human thyroid cancer. Oncologist. 2011;16(3):296-309. doi: 10.1634/theoncologist.2010-0317. Epub 2011 Feb 25. PubMed PMID: 21355020; PubMed Central PMCID: PMC3073446.

6: Nehs MA, Nagarkatti S, Nucera C, Hodin RA, Parangi S. Thyroidectomy with neoadjuvant PLX4720 extends survival and decreases tumor burden in an orthotopic mouse model of anaplastic thyroid cancer. Surgery. 2010 Dec;148(6):1154-62; discussion 1162. doi: 10.1016/j.surg.2010.09.001. PubMed PMID: 21134546; PubMed Central PMCID: PMC3413092.

7: Jiang CC, Lai F, Thorne RF, Yang F, Liu H, Hersey P, Zhang XD. MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res. 2011 Feb 15;17(4):721-30. doi: 10.1158/1078-0432.CCR-10-2225. Epub 2010 Nov 18. PubMed PMID: 21088259.

8: Kaplan FM, Shao Y, Mayberry MM, Aplin AE. Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. Oncogene. 2011 Jan 20;30(3):366-71. doi: 10.1038/onc.2010.408. Epub 2010 Sep 6. PubMed PMID: 20818433.