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| 25mg |
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Purity: ≥98%
Naporafenib (LXH254; LXH-254), extracted from patent WO2018051306A1, compound A, is a novel, potent and orally bioavailable C-RAF inhibitor with anticancer activity. Furthermore, it is a strong B-RAF inhibitor. LXH254 is a type II ATP-competitive inhibitor that exhibits high selectivity against a panel of 456 human kinases and in cell-based assays, inhibiting both B- and CRAF kinase activities at picomolar concentrations. Due to its capacity to inhibit both RAF monomers and dimers with comparable potencies, LXH254 not only inhibits MAPK signaling activity in tumor models harboring the BRAFV600 mutation, but it also inhibits mutant N- and KRAS-driven signaling. LXH254 is orally bioavailable, exhibits a direct PK/PD relationship, and, at well-tolerated doses, induces tumor regression in a variety of cell line and primary human tumor derived xenograft models. LXH254 represents a next generation RAF inhibitor that is differentiated from other RAF inhibitors in this class due to the high degree of selectivity. LXH254 showed a relatively wide therapeutic index in preclinical efficacy and toxicology studies, which should enable effective investigation of RAF inhibition in patients with lowered risk for off-target toxicity. Patients with solid tumors that express MAPK pathway mutations are currently enrolling in a Phase I trial for LXH254. All serine/threonine protein kinase Raf family members that have potential anticancer activity are inhibited by LXH254. The pan-RAF inhibitor LXH254 binds to Raf proteins and blocks Raf-mediated signal transduction pathways. Raf-overexpressed tumor cells are prevented from proliferating as a result. Raf protein kinases, which are upregulated in a number of cancer cell types, are essential enzymes in the Ras/Raf/MEK/ERK signaling pathway.
| Targets |
CRAF (IC50 = 0.072 nM); Braf (IC50 = 0.21 nM); ARAF (IC50 = 6.4 nM); p38α (IC50 = 2.1 μM); Abl1 (IC50 = 4.9 μM)
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| ln Vitro |
LXH254 (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. LXH254 is also referred to as a C-RAF/c-Raf kinase inhibitor and as a c-RAF (or CRAF) inhibitor throughout the present disclosure. In cell-based assays, LXH254 has proven to have anti-proliferative effects in cell lines with a variety of mutations that stimulate MAPK signaling. Additionally, LXH254 is a Type 2 ATP-competitive inhibitor of both B-Raf and C-Raf that maintains the kinase pocket in an inactive conformation, reducing the paradoxical activation seen with many B-Raf inhibitors and inhibiting mutant RAS-driven signaling and cell proliferation[1].
LXH254 (0–10 µM, 1 h) inhibits monomeric and dimeric RAF and encourages the formation of RAF dimers[2]. The ability of LXH254 to inhibit MAPK signaling driven by ARAF is decreased, and it has also been shown that when CRAF expression is absent, ARAF's contribution to MAPK signaling increases[2]. LXH254 shows more sensitivity when cells lack ARAF[2]. |
| ln Vivo |
In a number of KRAS-mutant models, including the NSCLC-derived Calu-6 (KRAS Q61K) and NCI-H358 (KRAS G12C), treatment with LXH254 (Compound A) results in tumor regression. Numerous MAPK-driven human cancer cell lines and xenograft tumors that represent model tumors with human lesions in the KRAS, NRAS, and BRAF oncogenes show efficacy for LXH254[1].
In models with BRAF mutations, whether they are present alone or in combination with activated NRAS or KRAS, LXH254 exhibits significant antitumor activity, and RAS mutants deficient in ARAF are more responsive to LXH254[2]. |
| Cell Assay |
For 3-day experiments involving crystal violet staining, cells were seeded in 6-well plates at a density of 50,000–100,000 cells/well, and the vehicle or drug (diluted in media) was added the next day.
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| Animal Protocol |
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]
100 mg/kg Orally, daily |
| References | |
| Additional Infomation |
Naporafenib is an orally available inhibitor of all members of the serine/threonine protein kinase Raf family, with potential antineoplastic activity. Upon administration, naporafenib binds to Raf proteins and inhibits Raf-mediated signal transduction pathways. This inhibits proliferation of Raf-overexpressing tumor cells. Raf protein kinases are critical enzymes in the Ras/Raf/MEK/ERK signaling pathway and are upregulated in a variety of cancer cell types. They play key roles in tumor cell proliferation and survival.
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| Molecular Formula |
C25H25F3N4O4
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|---|---|
| Molecular Weight |
502.4856
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| Exact Mass |
502.49
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| Elemental Analysis |
C, 59.76; H, 5.01; F, 11.34; N, 11.15; O, 12.74
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| CAS # |
1800398-38-2
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| Related CAS # |
1800398-38-2;LXH254 HCl;
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| PubChem CID |
90456533
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
709
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
UEPXBTCUIIGYCY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H25F3N4O4/c1-16-2-3-19(30-24(34)17-4-5-29-21(12-17)25(26,27)28)15-20(16)18-13-22(32-6-9-35-10-7-32)31-23(14-18)36-11-8-33/h2-5,12-15,33H,6-11H2,1H3,(H,30,34)
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| Chemical Name |
N-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-ylpyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide
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| Synonyms |
LXH-254; Naporafenib; LXH254; LXH 254
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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 (~199.0 mM)
Ethanol: ~100 mg/mL (~199.0 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.98 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.98 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.98 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2.5 mg/mL (4.98 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 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 |
*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 |
| NCT04417621 | Active Recruiting |
Drug: LXH254 Drug: LTT462 |
Melanoma | Novartis Pharmaceuticals | October 30, 2020 | Phase 2 |
| NCT02974725 | Active Recruiting |
Drug: LXH254 Drug: LTT462 |
Non-Small Cell Lung Cancer Melanoma |
Novartis Pharmaceuticals | February 24, 2017 | Phase 1 |
| NCT04294160 | Active Recruiting |
Drug: Dabrafenib Drug: LTT462 |
BRAF V600 Colorectal Cancer | Novartis Pharmaceuticals | July 22, 2020 | Phase 1 |
| NCT03333343 | Active Recruiting |
Drug: EGF816 Drug: trametinib |
EGFR-mutant Non-small Cell Lung Cancer |
Novartis Pharmaceuticals | January 29, 2018 | Phase 1 |
| NCT05907304 | Recruiting | Drug: Naporafenib Drug: Trametinib |
Advanced or Metastatic Solid Tumors |
Erasca, Inc. | August 17, 2023 | Phase 1 |
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