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MedKoo Cat#: 206480 | Name: PLX7904
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

PLX7904, also known as PB04, is a potent and selective paradox-breaker RAF inhibitor. PB04 is able to efficiently inhibit activation of ERK1/2 in mutant BRAF melanoma cells but does not hyperactivate ERK1/2 in mutant RAS-expressing cells. Importantly, PB04 inhibited ERK1/2 phosphorylation in mutant BRAF melanoma cells with acquired resistance to vemurafenib/PLX4720 that is mediated by a secondary mutation in NRAS. Consistent with ERK1/2 reactivation driving the re-acquisition of malignant properties, PB04 promoted apoptosis and inhibited entry into S phase and anchorage-independent growth in mutant N-RAS-mediated vemurafenib-resistant cells.

Chemical Structure

PLX7904
PLX7904
CAS#1393465-84-3

Theoretical Analysis

MedKoo Cat#: 206480

Name: PLX7904

CAS#: 1393465-84-3

Chemical Formula: C24H22F2N6O3S

Exact Mass: 512.1442

Molecular Weight: 512.54

Elemental Analysis: C, 56.24; H, 4.33; F, 7.41; N, 16.40; O, 9.36; S, 6.26

Price and Availability

Size Price Availability Quantity
10mg USD 110.00 Ready to ship
25mg USD 220.00 Ready to ship
50mg USD 385.00 Ready to ship
100mg USD 650.00 Ready to ship
200mg USD 1,050.00 Ready to ship
500mg USD 2,350.00 Ready to ship
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Synonym
PLX7904; PLX-7904; PLX 7904; PB04; PB-04; PB 04; paradox-breaker-04.
IUPAC/Chemical Name
5-(2-Cyclopropylpyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorobenzoyl]-1H-pyrrolo[2,3-b]pyridine
InChi Key
DKNZQPXIIHLUHU-UHFFFAOYSA-N
InChi Code
InChI=1S/C24H22F2N6O3S/c1-3-32(2)36(34,35)31-19-7-6-18(25)20(21(19)26)22(33)17-12-30-24-16(17)8-14(9-29-24)15-10-27-23(28-11-15)13-4-5-13/h6-13,31H,3-5H2,1-2H3,(H,29,30)
SMILES Code
O=C(C1=CNC2=NC=C(C3=CN=C(C4CC4)N=C3)C=C21)C5=C(F)C=CC(NS(=O)(N(CC)C)=O)=C5F
Appearance
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
>2 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
Biological target:
PLX7904, also known as PB04, is a potent and selective paradox-breaker RAF inhibitor. It is able to efficiently inhibit activation of ERK1/2 in mutant BRAF melanoma cells but does not hyperactivate ERK1/2 in mutant RAS-expressing cells.
In vitro activity:
Optimization by substitution on the 5-position of the 7-azaindole scaffold generated PLX7904 (Fig. 1a), which potently inhibited pERK in BRAFV600E cells but showed essentially no pERK activation in RAS mutant cell lines at the concentrations tested (Table 1, Fig. 1b and Extended Data Fig. 1). PLX7904 was also evaluated in the human SCC cell line A431 and the human breast adenocarcinoma cell line SKBR3 as these cells achieve MAPK pathway activation by upstream signals feeding into RAS (through overexpression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), respectively). PLX7904 did not increase pERK levels in these cells (Fig. 1c). In biochemical assays using recombinant kinases, PLX7904 showed preferential inhibition of the mutated BRAFV600E over wild-type BRAF and CRAF and a level of kinome selectivity comparable to that of vemurafenib13 (Supplementary Table 1). PLX7904 inhibited the in vitro growth of two aforementioned melanoma cell lines (A375 and COLO829) and an additional human colorectal cancer cell line COLO205 that expressed BRAFV600E with IC50 values of 0.17 mM, 0.53 mM, and 0.16 mM, respectively, on a par with vemurafenib IC50 values in the same assays (0.33 mM, 0.69 mM, and 0.25 mM, respectively). Reference: Nature. 2015 Oct 22;526(7574):583-6. https://doi.org/10.1038/nature14982
In vivo activity:
PLX7904 produced similar anti-tumour effects in a subcutaneous COLO205 xenograft model (Fig. 1e) with doses of 25 mg per kg twice daily and plasma exposures (steady-state area under the curve < 200,000 ng ml21 h). When tested in vivo, subcutaneous B9-tumour growth wasn’t accelerated by the potent BRAFV600E inhibitor PLX7904 (Fig. 1f). Reference: Nature. 2015 Oct 22;526(7574):583-6. https://doi.org/10.1038/nature14982
Solvent mg/mL mM comments
Solubility
DMSO 30.0 58.50
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 512.54 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. Le K, Blomain ES, Rodeck U, Aplin AE. Selective RAF inhibitor impairs ERK1/2 phosphorylation and growth in mutant NRAS, vemurafenib-resistant melanoma cells. Pigment Cell Melanoma Res. 2013 Jul;26(4):509-17. doi: 10.1111/pcmr.12092. Epub 2013 Apr 8. PMID: 23490205; PMCID: PMC3695051. 2. Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B, Tsang G, Marimuthu A, Cho H, Wu G, Wang W, Fong D, Nguyen H, Shi S, Womack P, Nespi M, Shellooe R, Carias H, Powell B, Light E, Sanftner L, Walters J, Tsai J, West BL, Visor G, Rezaei H, Lin PS, Nolop K, Ibrahim PN, Hirth P, Bollag G. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14. PMID: 26466569.
In vivo protocol:
1. Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B, Tsang G, Marimuthu A, Cho H, Wu G, Wang W, Fong D, Nguyen H, Shi S, Womack P, Nespi M, Shellooe R, Carias H, Powell B, Light E, Sanftner L, Walters J, Tsai J, West BL, Visor G, Rezaei H, Lin PS, Nolop K, Ibrahim PN, Hirth P, Bollag G. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14. PMID: 26466569.
1: Ngo VA. Insight into molecular basis and dynamics of full-length CRaf kinase in cellular signaling mechanisms. Biophys J. 2024 Aug 20;123(16):2623-2637. doi: 10.1016/j.bpj.2024.06.028. Epub 2024 Jun 29. PMID: 38946141; PMCID: PMC11365224. 2: Koumaki K, Kontogianni G, Kosmidou V, Pahitsa F, Kritsi E, Zervou M, Chatziioannou A, Souliotis VL, Papadodima O, Pintzas A. BRAF paradox breakers PLX8394, PLX7904 are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 and shown by detailed pathway analysis. Biochim Biophys Acta Mol Basis Dis. 2021 Apr 1;1867(4):166061. doi: 10.1016/j.bbadis.2020.166061. Epub 2020 Dec 29. PMID: 33385518. 3: Wang PF, Qiu HY, Zhu HL. A patent review of BRAF inhibitors: 2013-2018. Expert Opin Ther Pat. 2019 Aug;29(8):595-603. doi: 10.1080/13543776.2019.1640680. Epub 2019 Jul 13. PMID: 31280615. 4: Miyamoto K, Sawa M. Development of Highly Sensitive Biosensors of RAF Dimerization in Cells. Sci Rep. 2019 Jan 24;9(1):636. doi: 10.1038/s41598-018-37213-2. PMID: 30679688; PMCID: PMC6345758. 5: Roskoski R Jr. Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol Res. 2018 Sep;135:239-258. doi: 10.1016/j.phrs.2018.08.013. Epub 2018 Aug 15. PMID: 30118796. 6: Tutuka CSA, Andrews MC, Mariadason JM, Ioannidis P, Hudson C, Cebon J, Behren A. PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation. Mol Cancer. 2017 Jun 28;16(1):112. doi: 10.1186/s12943-017-0684-x. PMID: 28659148; PMCID: PMC5490236. 7: Tse A, Verkhivker GM. Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways. PLoS One. 2016 Nov 18;11(11):e0166583. doi: 10.1371/journal.pone.0166583. PMID: 27861609; PMCID: PMC5115767. 8: Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B, Tsang G, Marimuthu A, Cho H, Wu G, Wang W, Fong D, Nguyen H, Shi S, Womack P, Nespi M, Shellooe R, Carias H, Powell B, Light E, Sanftner L, Walters J, Tsai J, West BL, Visor G, Rezaei H, Lin PS, Nolop K, Ibrahim PN, Hirth P, Bollag G. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14. PMID: 26466569. 9: Basile KJ, Le K, Hartsough EJ, Aplin AE. Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell Melanoma Res. 2014 May;27(3):479-84. doi: 10.1111/pcmr.12218. Epub 2014 Feb 10. PMID: 24422853; PMCID: PMC3988223. 10: Le K, Blomain ES, Rodeck U, Aplin AE. Selective RAF inhibitor impairs ERK1/2 phosphorylation and growth in mutant NRAS, vemurafenib-resistant melanoma cells. Pigment Cell Melanoma Res. 2013 Jul;26(4):509-17. doi: 10.1111/pcmr.12092. Epub 2013 Apr 8. PMID: 23490205; PMCID: PMC3695051.