2. MAPK/ERK Pathway Protein Tyrosine Kinase/RTK
  3. Raf p38 MAPK Bcr-Abl
  4. Naporafenib

Naporafenib  (Synonyms: LXH254)

Cat. No.: HY-112089 Purity: 99.86%
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Naporafenib (LXH254) is a potent, selective, orally active, type II BRAF and CRAF inhibitor, with IC50 values of 0.072 and 0.21 nM against CRAF and BRAF, respectively.

For research use only. We do not sell to patients.

Naporafenib Chemical Structure

Naporafenib Chemical Structure

CAS No. : 1800398-38-2

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Solid + Solvent (Highly Recommended)
10 mM * 1 mL in DMSO
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Customer Review

Based on 5 publication(s) in Google Scholar

Naporafenib Related Antibodies

Top Publications Citing Use of Products

View All Raf Isoform Specific Products:

View All Isoforms
BRaf c-Raf Raf

View All p38 MAPK Isoform Specific Products:

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p38 MAPK p38α p38β MAPK13 p38δ p38γ

  • Biological Activity

  • Purity & Documentation

  • References

  • Customer Review

Description

Naporafenib (LXH254) is a potent, selective, orally active, type II BRAF and CRAF inhibitor, with IC50 values of 0.072 and 0.21 nM against CRAF and BRAF, respectively[1][2].

IC50 & Target[1]

CRAF

0.072 nM (IC50)

Braf

0.21 nM (IC50)

ARAF

6.4 nM (IC50)

p38α

2.1 μM (IC50)

Abl1

4.9 μM (IC50)

Cellular Effect
Cell Line Type Value Description References
Calu-6 EC50
0.28 μM
Compound: 15; LXH254
Antiproliferative activity against human Calu6 cells harboring KRAS Q61K mutant assessed as reduction in cell viability after 72 hrs by CellTiter-Glo assay
Antiproliferative activity against human Calu6 cells harboring KRAS Q61K mutant assessed as reduction in cell viability after 72 hrs by CellTiter-Glo assay
[PMID: 31059256]
NCI-H358 GI50
3 μM
Compound: LXH254
Growth inhibition of human H358 cells expressing KRAS G21C mutant measured after 3 days by Cell-titer Glo assay
Growth inhibition of human H358 cells expressing KRAS G21C mutant measured after 3 days by Cell-titer Glo assay
[PMID: 35276360]
NCI-H358 GI50
3 μM
Compound: LXH254
Cytotoxicity against human NCI-H358 cells assessed as inhibition of growth measured after 72 hrs by CellTiter-Glo luciferase assay
Cytotoxicity against human NCI-H358 cells assessed as inhibition of growth measured after 72 hrs by CellTiter-Glo luciferase assay
[PMID: 34906761]
In Vitro

Naporafenib (Compound A) is an adenosine triphosphate (ATP)-competitive inhibitor of BRAF (also referred to herein as b-RAF or b-Raf) and CRAF (also referred to herein as c-RAF or c- Raf) protein kinases. Throughout the present disclosure, Naporafenib is also referred to as a c-RAF (or CRAF) inhibitor or a C-RAF/c-Raf kinase inhibitor. In cell-based assays, Naporafenib has demonstrated anti-proliferative activity in cell lines that contain a variety of mutations that activate MAPK signaling. Moreover, Naporafenib is a Type 2 ATP -competitive inhibitor of both B-Raf and C-Raf that keeps the kinase pocket in an inactive conformation, thereby reducing the paradoxical activation seen with many B-Raf inhibitors, and blocking mutant RAS-driven signaling and cell proliferation[1].
Naporafenib (0-10 µM, 1 h) inhibits both monomeric and dimeric RAF and promotes RAF dimer formation[2].
Naporafenib has reduced ability to suppress MAPK signaling driven by ARAF and further that the contribution of ARAF to MAPK signaling increases in the absence of CRAF expression[2].
Naporafenib shows more sensitivity when cells lack ARAF[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Naporafenib Related Antibodies

Western Blot Analysis[2]

Cell Line: HCT116, MEL-JUSO, Mia PaCa-2, A375(BRAFV600E), and HCT116 (KRASG13D)
Concentration: 0-10 µM
Incubation Time: 1 h
Result: Promoted B/CRAF heterodimer formation. Displayed similar inhibition of monomeric BRAFV600 and wild-type dimeric RAF (IC50 for p-ERK levels of 59 and 78 nmol/L in A-375 and HCT 116 cells, respectively).

Cell Proliferation Assay[2]

Cell Line: Two NRAS-mutant melanoma cell lines (MEL-JUSO and SK-MEL-30), three KRAS-mutant cell lines (COR-L23, MIA PaCa-2, and HCT116), and derived variants lacking expression of either ARAF, BRAF, or CRAF.
Concentration: 0-10 µM
Incubation Time: 24 h
Result: The sensitivity was increased relative to parental cell lines in all models tested by loss of ARAF expression.
In Vivo

Treatment with Naporafenib (Compound A) generates tumor regression in several KRAS-mutant models including the NSCLC-derived Calu-6 (KRAS Q61K) and NCI-H358 (KRAS G12C). Naporafenib exhibits efficacy in numerous MAPK-driven human cancer cell lines and in xenograft tumors representing model tumors harboring human lesions in KRAS, NRAS and BRAF oncogenes[1].
Naporafenib shows significant antitumor activity in models harboring BRAF mutations either alone or coincident with either activated NRAS or KRAS, and RAS mutants lacking ARAF are more sensitive to Naporafenib[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Outbred athymic (nu/nu) female mice and SCID Beige mice; BRAF-, NRAS-, and KRAS-mutant xenograft models, as well as a RAS/RAF wild-type model[2]
Dosage: 100 mg/kg
Administration: Orally, daily
Result: Significantly decreased tumor volume in models harboring BRAF mutations either alone or coincident with either activated NRAS or KRAS, slightly decreased tumor volume in KRAS model.
Clinical Trial
Molecular Weight

502.49

Formula

C25H25F3N4O4
CAS No.
Appearance

Solid

Color

Off-white to light yellow

SMILES

CC1=CC=C(NC(C2=CC(C(F)(F)F)=NC=C2)=O)C=C1C3=CC(N4CCOCC4)=NC(OCCO)=C3
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 1 year
-20°C 6 months
Solvent & Solubility
In Vitro: 

DMSO : 100 mg/mL (199.01 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 1.9901 mL 9.9504 mL 19.9009 mL
5 mM 0.3980 mL 1.9901 mL 3.9802 mL
View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 1 year; -20°C, 6 months. When stored at -80°C, please use it within 1 year. When stored at -20°C, please use it within 6 months.

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Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Mass
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Concentration
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Volume
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Molecular Weight *

Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

This equation is commonly abbreviated as: C1V1 = C2V2

Concentration (start)

C1

×
Volume (start)

V1

=
Concentration (final)

C2

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Volume (final)

V2

In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

  • Protocol 1

    Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

    Solubility: ≥ 2.5 mg/mL (4.98 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

    Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
  • Protocol 2

    Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in Saline)

    Solubility: ≥ 2.5 mg/mL (4.98 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

    Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:

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(per animal)

g

Dosing volume
(per animal)

μL

Number of animals

Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
%
DMSO +
% 
+
%
Tween-80 +
%
Saline
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration: mg/mL
Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
 If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Purity & Documentation

Purity: 99.86%

SDS (251 KB)

COA (251 KB) HNMR (274 KB) LCMS (93 KB)

Handling Instructions (2659 KB)
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 1 year; -20°C, 6 months. When stored at -80°C, please use it within 1 year. When stored at -20°C, please use it within 6 months.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 1.9901 mL 9.9504 mL 19.9009 mL 49.7522 mL
5 mM 0.3980 mL 1.9901 mL 3.9802 mL 9.9504 mL
10 mM 0.1990 mL 0.9950 mL 1.9901 mL 4.9752 mL
15 mM 0.1327 mL 0.6634 mL 1.3267 mL 3.3168 mL
20 mM 0.0995 mL 0.4975 mL 0.9950 mL 2.4876 mL
25 mM 0.0796 mL 0.3980 mL 0.7960 mL 1.9901 mL
30 mM 0.0663 mL 0.3317 mL 0.6634 mL 1.6584 mL
40 mM 0.0498 mL 0.2488 mL 0.4975 mL 1.2438 mL
50 mM 0.0398 mL 0.1990 mL 0.3980 mL 0.9950 mL
60 mM 0.0332 mL 0.1658 mL 0.3317 mL 0.8292 mL
80 mM 0.0249 mL 0.1244 mL 0.2488 mL 0.6219 mL
100 mM 0.0199 mL 0.0995 mL 0.1990 mL 0.4975 mL
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Naporafenib Related Classifications

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  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

Naporafenib1800398-38-2LXH254LXH 254LXH-254Rafp38 MAPKBcr-AblRaf kinasesSelectiveHCT116MEL-JUSOMia PaCa-2A375Inhibitorinhibitorinhibit

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