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Purity: =98.1%
PLX8394 (PLX-8394) is a novel, potent, orally bioavailable and selective inhibitor of the serine/threonine-protein kinase B-raf (BRaf) with anticancer activity. With an approximate 5 nM IC50 for BRAFV600E, it inhibits BRAF. In BRAF-mutant LA models, PLX8394 can avoid the reactivation of the MAPK pathway. Treatment with PLX8394 is successful in vitro and in vivo in BRAFV600E and some non-V600 LA models. Treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance brought on by an alternatively spliced, truncated BRAFV600E that encourages vemurafenib-insensitive MAPK pathway signaling were both successfully treated with PLX8394. A combination therapy that includes PLX8394 and either an EGFR or mTOR inhibitor up front can prevent acquired PLX8394 resistance, which is caused by EGFR-mediated RAS-mTOR signaling. This study offers a biological justification and potential polytherapy plan to support the administration of PLX8394 to patients with lung cancer. By encouraging mitogen-activated protein kinase (MAPK) pathway signaling, oncogenic activation of the protein kinase BRAF promotes tumor growth. BRAF-mutant lung adenocarcinoma (LA) is the most common cause of BRAF-mutant cancer mortality globally because oncogenic mutations in BRAF occur in ~2-7% of LA. However, the spectrum of BRAF mutations in LA includes both BRAFV600E (60% of cases) and non-V600E mutant alleles (~40% of cases), such as BRAFG469A and BRAFG466V. Unlike most tumor types, which primarily harbor the BRAFV600E-mutant allele, LA tumors primarily harbor the BRAFV600E-mutant allele. Clinical trials testing selective BRAF inhibitors, like vemurafenib, in BRAFV600E-mutant patients have been prompted by the presence of BRAFV600E in LA. Despite showing some clinical promise, reactivation of the MAPK pathway signaling frequently leads to both innate and acquired resistance, which limits the long-lasting effects of the available BRAF inhibitors. Furthermore, the ideal therapeutic approach to stop non-V600E BRAF-mutant LA is still unknown.
Targets |
BRAF(V600E) (IC50 = 3.8 nM); BRAF (IC50 = 14 nM); CRAF (IC50 = 23 nM)
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ln Vitro |
PLX8394 is a next-generation, orally available small-molecule BRAFi that inhibits both monomeric and dimeric BRAFV600 and BRAFnon-V600 protein signaling and does not cause the RAF/MEK/ERK paradoxical activation[1].
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ln Vivo |
PLX8394 is a small molecule BRAF inhibitor of the newest generation that can be taken orally and has antineoplastic potential.
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Cell Assay |
For 6 hours, cells were exposed to DMSO, vemurafenib at 1 μM, or PLX8394 at 1 μM.
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References |
Molecular Formula |
C25H21F3N6O3S
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Molecular Weight |
542.5329
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Exact Mass |
542.13
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Elemental Analysis |
C, 55.35; H, 3.90; F, 10.51; N, 15.49; O, 8.85; S, 5.91
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CAS # |
1393466-87-9
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Related CAS # |
1393466-87-9 (PLX8394); 1652573-86-8 (PLX7683, a paradox breaker); 918505-61-0 (Vemurafenib/ PLX4032 analog)
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Appearance |
White to off-white solid powder
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SMILES |
C1CN(C[C@@H]1F)S(=O)(=O)NC2=C(C(=C(C=C2)F)C(=O)C3=CNC4=C3C=C(C=N4)C5=CN=C(N=C5)C6CC6)F
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InChi Key |
YYACLQUDUDXAPA-MRXNPFEDSA-N
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InChi Code |
InChI=1S/C25H21F3N6O3S/c26-16-5-6-34(12-16)38(36,37)33-20-4-3-19(27)21(22(20)28)23(35)18-11-32-25-17(18)7-14(8-31-25)15-9-29-24(30-10-15)13-1-2-13/h3-4,7-11,13,16,33H,1-2,5-6,12H2,(H,31,32)/t16-/m1/s1
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Chemical Name |
(3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide
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Synonyms |
PLX-8394; PLX 8394; PLX8394
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
DMSO: ~100 mg/mL (~184.3 mM)
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Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 :Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.8432 mL | 9.2161 mL | 18.4322 mL | |
5 mM | 0.3686 mL | 1.8432 mL | 3.6864 mL | |
10 mM | 0.1843 mL | 0.9216 mL | 1.8432 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT02012231 | Terminated | Drug: PLX8394 | Melanoma Histiocytosis |
Fore Biotherapeutics | February 2014 | Phase 1 |
Effect of the BRAF inhibitors vemurafenib and PLX8394 on the MAPK pathway in colorectal cancer cell lines. Mol Cancer . 2017 Jun 28;16(1):112. td> |
The effect of vemurafenib and PLX8394 on proliferation and survival of BRAF wt / KRAS G12D and BRAF V600E / KRAS wt colorectal cancer cell lines. Mol Cancer . 2017 Jun 28;16(1):112. td> |