Naporafenib (Synonyms: LXH254)

Name: Naporafenib
Brand: MedChemExpress
SKU: HY-112089
Rating: 5.0 (5 reviews)

Cat. No.: HY-112089 Purity: 99.92%: Data Sheet
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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.

CAS No. : 1800398-38-2

Size	Stock	Quantity

Free Sample (0.1 - 0.2 mg)	Apply Now
Solid + Solvent (Highly Recommended)
10 mM * 1 mL in DMSO ready for reconstitution	In-stock	Estimated Time of Arrival: December 31
Solution
10 mM * 1 mL in DMSO	In-stock	Estimated Time of Arrival: December 31
Solid
2 mg	In-stock	Estimated Time of Arrival: December 31
5 mg	In-stock	Estimated Time of Arrival: December 31
10 mg	In-stock	Estimated Time of Arrival: December 31
25 mg	In-stock	Estimated Time of Arrival: December 31
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Customer Review

Based on 5 publication(s) in Google Scholar

5 Publications Citing Use of MCE Naporafenib

Bio/Physico-chemical Assay

PK/PD Analysis

: Naporafenib purchased from MedChemExpress. Usage Cited in: Patent. US20240239801A1.; Naporafenib (LXH254) exhibited an IC₅₀ of >20 nM for ARAF kinase.

: Naporafenib purchased from MedChemExpress. Usage Cited in: Biomed Chromatogr. 2021 Feb;35(2):e4968. [Abstract]; Plasma concentration-time profiles of Naporafenib (LXH254) in rat plasma after intravenous (2 mg/kg) administration.

: Naporafenib purchased from MedChemExpress. Usage Cited in: Biomed Chromatogr. 2021 Feb;35(2):e4968. [Abstract]; Pharmacokinetic parameters of Naporafenib (LXH254) in rats after intravenous administration
Note. Data are expressed as mean ± standard deviation (n = 6). AUC, area under the plasma concentration–time curve; CL, clearance; MRT, mean residence time.

: Naporafenib purchased from MedChemExpress. Usage Cited in: Biomed Chromatogr. 2021 Feb;35(2):e4968. [Abstract]; Plasma concentration-time profiles of Naporafenib (LXH254) in rat plasma after oral (2, 5, and 15 mg/kg) administrations.

: Naporafenib purchased from MedChemExpress. Usage Cited in: Biomed Chromatogr. 2021 Feb;35(2):e4968. [Abstract]; Pharmacokinetic parameters of Naporafenib (LXH254) in rats after oral administration
Note. Data are expressed as mean ± standard deviation (n = 6). AUC, area under the plasma concentration–time curve; CL, clearance; MRT, mean residence time.

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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
A-375	IC₅₀	0.24 μM Compound: 14, LXH254	Antiproliferative activity against human A-375 cells Antiproliferative activity against human A-375 cells	[PMID: 32910655]
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	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]
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]

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.

Western Blot Analysis^[2]

Cell Line:	HCT116, MEL-JUSO, Mia PaCa-2, A375(BRAF^V600E), and HCT116 (KRAS^G13D)
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.

1800398-38-2

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
10 mM	0.1990 mL	0.9950 mL	1.9901 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.

Molarity Calculator
Dilution Calculator

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

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

This equation is commonly abbreviated as: C₁V₁ = C₂V₂

Concentration _(start)

Volume _(start)

Concentration _(final)

Volume _(final)

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.
Protocol 3

Add each solvent one by one: 10% DMSO 90% Corn Oil
Solubility: ≥ 2.5 mg/mL (4.98 mM); Clear solution

This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL Corn oil, and mix evenly.
Protocol 4

Add each solvent one by one: 5% DMSO 40% PEG300 5% Tween-80 50% Saline
Solubility: 2.5 mg/mL (4.98 mM); Suspended solution; Need ultrasonic

In Vivo Dissolution Calculator

Please enter the basic information of animal experiments:

Dosage

mg/kg

Animal weight
(per animal)

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: 99.92%

Select Batch:

Data Sheet (282 KB) SDS (393 KB)

COA (251 KB) HNMR (137 KB) RP-HPLC (244 KB) LCMS (106 KB)

Handling Instructions (2659 KB)

References

[1]. CAPONIGRO, Giordano, et al. THERAPEUTIC COMBINATIONS COMPRISING A RAF INHIBITOR AND A ERK INHIBITOR. WO 2018051306 A1 20180322

[2]. Kelli-Ann Monaco, et al. LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors. Clin Cancer Res. 2021 Apr 1;27(7):2061-2073. [Content Brief]

Complete Stock Solution Preparation Table

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

Naporafenib Related Classifications

Help & FAQs

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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Naporafenib (Synonyms: LXH254)

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Naporafenib Related Antibodies

5 Publications Citing Use of MCE Naporafenib

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Customer Review

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Complete Stock Solution Preparation Table

Naporafenib Related Classifications

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