Capmatinib Chemical Properties

Melting point:

>250°C (dec.)

Density 

1.40

vapor pressure 

0-0Pa at 20-25℃

storage temp. 

-20°C Freezer, Under inert atmosphere

solubility 

DMSO (Slightly), Methanol (Slightly)

pka

13.82±0.46(Predicted)

form 

Solid

color 

Pale Yellow to Light Yellow

InChI

InChI=1S/C23H17FN6O/c1-25-22(31)18-6-5-16(11-19(18)24)21-13-28-23-27-12-17(30(23)29-21)10-14-4-7-20-15(9-14)3-2-8-26-20/h2-9,11-13H,10H2,1H3,(H,25,31)

InChIKey

LIOLIMKSCNQPLV-UHFFFAOYSA-N

SMILES

C(NC)(=O)C1=CC=C(C2=NN3C(CC4=CC=C5C(=C4)C=CC=N5)=CN=C3N=C2)C=C1F

LogP

1.6-2.2 at 35℃ and pH7-9

Capmatinib Usage And Synthesis

MET small molecule inhibitor

Capmatinib(Synonyms: INC280; INCB28060) is a competitive inhibitor with very potent and selective activity against MET compared to other kinases. It has been shown in vitro that cell lines made resistant to erlotinib, an EGFR inhibitor, could be resensitized after capmatinib treatment. Results from a phase Ib/II study of patients with EGFR-mutated, MET-dysregulated NSCLC have shown promising responses to a combination of capmatinib and gefitinib (EGFR TKI) following disease progression from an only EGFR TKI treatment regimen. Recommended phase II dose was determined to be capmatinib 400 mg twice/day and gefitinib 250 mg once/day. Most common adverse events were nausea, peripheral edema, decreased appetite, rash, and increased amylase and lipase levels.

Originator

Novartis

Description

INCB 28060 is an inhibitor of heptatocyte growth factor receptor (HGFR, also known as c-Met), potently blocking in vitro kinase activity (IC₅₀ = 0.13 nM) as well as constitutive or HGF-stimulated activity in cells (IC₅₀ values range from 0.3 to 1.1 nM). It blocks cell proliferation and migration or induces apoptosis in different types of cancer cells. INCB 28060 is orally bioavailable and inhibits the growth of HGFR-dependent tumors in mice. It also improves efficacy of gemcitabine in a mouse pancreatic cancer model and reduces migration and adhesion in ovarian cancer cell models.

Description

Capmatinib is a competitive inhibitor with very potent and selective activity against MET compared to other kinases.

Uses

2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide is used in the preparation of a combination formulation with allosteric SHP2 inhibitor TNO155. Used in treatment of non-small cell lung cancer with specific mutations (those that lead to mesenchymal-epithelial transition or MET exon 14 skipping).

brand name

Tabrecta

General Description

Class: receptor tyrosine kinase; Treatment: NSCLC with METex14; Other name: INCB28060; Oral bioavailability >70%; Elimination half-life = 7.8 h; Protein binding = 96%

Side effects

Most common adverse events were nausea, peripheral edema, decreased appetite, rash, and increased amylase and lipase levels.

Synthesis

Example 20 Synthesis of 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15): 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzoic acid (14, 331.4 g, 0.914 mol, 1.0 eq.) and (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyBOP, 570 g, 1.1 mol, 1.2 eq.) were dissolved in N,N-dimethylformamide (DMF, 3700 mL). To this solution, a tetrahydrofuran solution of 2M methylamine (1830 mL, 3.656 mol, 4.0 eq.) was slowly added for 15 min at room temperature. The reaction temperature was raised to 30 °C during the addition and the reaction mixture became homogeneous. Subsequently, triethylamine (TEA, 382 mL, 2.742 mol, 3.0 eq.) was added to the reaction mixture and the reaction mixture was stirred for 2-4 h at room temperature. The progress of the reaction was monitored by LC/MS and after confirming the completion of the coupling reaction, water (950 mL) was added to the reaction mixture. The resulting suspension was cooled to 0-5 °C in an ice bath and stirred at this temperature for 30 min. The solid was collected by filtration and washed with water (200 mL). The wet solid filter cake was suspended in a solvent mixture of water and acetonitrile (1:1 v/v, 2000 mL) and stirred for 1 hour at room temperature. The solid was collected by filtration, washed sequentially with water and acetonitrile, and then dried to constant weight in a vacuum oven at 40-45 °C to afford 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15, 322 g, 85.4% yield) as a yellow to bright yellow powder.

in vitro

It has been shown in vitro that cell lines made resistant to erlotinib, an EGFR inhibitor, could be resensitized after capmatinib treatment. Results from a phase Ib/II study of patients with EGFR-mutated, MET-dysregulated NSCLC have shown promising responses to a combination of capmatinib and gefitinib (EGFR TKI) following disease progression from an only EGFR TKI treatment regimen. Recommended phase II dose was determined to be capmatinib 400 mg twice/day and gefitinib 250 mg once/day.

target

c-MET

References

1. liu x, wang q, yang g, et al. a novel kinase inhibitor, incb28060, blocks c-met-dependent signaling, neoplastic activities, and cross-talk with egfr and her-3. clinical cancer research : an official journal of the american association for cancer research. 2011;17(22):7127-7138.

Capmatinib(1029712-80-8)Related Product Information

• AP26113
• Lenvatinib
• Afatinib (BIBW 2992)
• Vandetanib
• Ceritinib
• Selumetinib
• GSK1838705A
• Dasatinib
• SGX-523
• Crizotinib
• Lorlatinib (PF-06463922)
• BKM-120
• INCB28060 Dihydrochloride
• Cabozantinib
• WZ4002
• Dabrafenib
• Dacomitinib (PF299804)
• 1110813-31-4