WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205494
CAS#: 1029712-80-8 (free base)
Description: Capmatinib, also known as INCB28060 and INC280, is an orally bioavailable inhibitor of the proto-oncogene c-Met (hepatocyte growth factor receptor [HGFR]) with potential antineoplastic activity. c-Met inhibitor INC280 selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met protein or expressing constitutively activated c-Met protein. Capmatinib was approved in 2020.
MedKoo Cat#: 205494
CAS#: 1029712-80-8 (free base)
Chemical Formula: C23H17FN6O
Exact Mass: 412.14479
Molecular Weight: 412.42
Elemental Analysis: C, 66.98; H, 4.15; F, 4.61; N, 20.38; O, 3.88
Synonym: INC280; INC-280; INC 280; INCB028060; INCB-028060; INCB 028060; INCB28060; INCB-28060; INCB 28060; Capmatinib.
IUPAC/Chemical Name: 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide
InChi Key: LIOLIMKSCNQPLV-UHFFFAOYSA-N
InChi Code: 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)
SMILES Code: O=C(NC)C1=CC=C(C2=NN3C(N=C2)=NC=C3CC4=CC=C5N=CC=CC5=C4)C=C1F
Appearance: Yellow solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||ATP competitive c-Met kinase inhibitor (IC50=0.13 nM)|
|In vitro activity:||Pancreatic cancer is characterized by a strong stromal reaction. Therefore, the effects of cMET inhibition on ECs and VSMCs were examined. MTT assays in ECs under serum-starved conditions and stimulation with HGF, showed a slight but significant increase in growth that was diminished by INC280 (Capmatinib) (Additional file 3: Figure S3B). No effect upon constitutive conditions was observed (Additional file 3: Figure S3A). EC motility was significantly increased upon incubation with HGF, which was strongly reduced by INC280 (Figure 4A). Regarding activation of signaling pathways, treatment with INC280 strongly inhibited HGF-induced activation of Akt and ERK whereas no effects on constitutive Akt and ERK phosphorylation were found (Figure 4B). Taken together, these results show that INC280 affects ECs only when these cells are stimulated with HGF. Next we analyzed the impact of INC280 on VSMCs. MTT assays showed a dose-dependent inhibition of VSMC growth starting from INC280 (100nM) after 72 hours of incubation (Additional file 3: Figure S3C). In contrast to ECs, stimulation with HGF upon serum-starved conditions had no effect on VSMC growth and, accordingly, INC280 did not have a further growth inhibitory effect in MTT assays (Additional file 3: Figure S3D). Motility upon incubation with HGF in VSMCs was not induced, but targeting cMET with INC280 led to a significant inhibition of constitutive migration (Figure 4C). Finally, Western blotting did not show a substantial effect of INC280 on constitutive Akt phosphorylation and only a minor impact on ERK phosphorylation in VSMCs (Figure 4D). These results indicate that HGF does not affect VSMCs and cMET inhibition with INC280, therefore, has only minor effects on these cells. Reference: BMC Cancer. 2015; 15: 71. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340491/|
|In vivo activity:||Tumors underwent a histological examination by a pathologist to determine phenotype and progression. Of the WT mice fed normal diet there were a total of 16 tumors. Twelve of the tumors were papillomas, with one converting to a squamous cell carcinoma (Fig.4d). Three additional tumors were cutaneous lipomas. This is in comparison to Tpl2 −/− mice which had a total of 61 tumors, 51 papillomas, four SCCs, three sebaceous adenomas, and three lipomas. In contrast, no Tpl2 −/− mice fed capmatinib diet had papillomas convert to SCCs (Fig. (Fig.4d).4d). Although Tpl2 −/− mice develop an overall higher tumor burder, there were no statistical differences in tumor size between genotypes and the rate of malignant conversion (7.8 vs. 8.3%) was similar between Tpl2 −/− and WT mice on normal diet. However, the rate of malignant conversion between Tpl2 −/− mice on normal diet (8.3%) vs. Tpl2 −/− mice on Capmatinib diet (0%) was significantly different (p < 0.01). In both genotypes male mice developed more tumors than female mice (Fig.4e; p < 0.05). Reference: Oncogenesis. 2019 Jan; 8(1): 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328619/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
|DMF:PBS (pH 7.2) (1:3)||0.25||0.61|
The following data is based on the product molecular weight 412.42 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|Formulation protocol:||1. Brandes F, Schmidt K, Wagner C, Redekopf J, Schlitt HJ, Geissler EK, Lang SA. Targeting cMET with INC280 impairs tumour growth and improves efficacy of gemcitabine in a pancreatic cancer model. BMC Cancer. 2015 Feb 19;15:71. doi: 10.1186/s12885-015-1064-9. PMID: 25884642; PMCID: PMC4340491. 2. Bonan NF, Kowalski D, Kudlac K, Flaherty K, Gwilliam JC, Falkenberg LG, Maradiaga E, DeCicco-Skinner KL. Inhibition of HGF/MET signaling decreases overall tumor burden and blocks malignant conversion in Tpl2-related skin cancer. Oncogenesis. 2019 Jan 10;8(1):1. doi: 10.1038/s41389-018-0109-8. PMID: 30631034; PMCID: PMC6328619.|
|In vitro protocol:||1. Brandes F, Schmidt K, Wagner C, Redekopf J, Schlitt HJ, Geissler EK, Lang SA. Targeting cMET with INC280 impairs tumour growth and improves efficacy of gemcitabine in a pancreatic cancer model. BMC Cancer. 2015 Feb 19;15:71. doi: 10.1186/s12885-015-1064-9. PMID: 25884642; PMCID: PMC4340491.|
|In vivo protocol:||1. Bonan NF, Kowalski D, Kudlac K, Flaherty K, Gwilliam JC, Falkenberg LG, Maradiaga E, DeCicco-Skinner KL. Inhibition of HGF/MET signaling decreases overall tumor burden and blocks malignant conversion in Tpl2-related skin cancer. Oncogenesis. 2019 Jan 10;8(1):1. doi: 10.1038/s41389-018-0109-8. PMID: 30631034; PMCID: PMC6328619.|
1: Vansteenkiste JF, Van De Kerkhove C, Wauters E, Van Mol P. Capmatinib for the treatment of non-small cell lung cancer. Expert Rev Anticancer Ther. 2019 Aug;19(8):659-671. doi: 10.1080/14737140.2019.1643239. Epub 2019 Aug 1. PMID: 31368815.
2: Wu YL, Zhang L, Kim DW, Liu X, Lee DH, Yang JC, Ahn MJ, Vansteenkiste JF, Su WC, Felip E, Chia V, Glaser S, Pultar P, Zhao S, Peng B, Akimov M, Tan DSW. Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR- Mutated, MET Factor-Dysregulated Non-Small-Cell Lung Cancer. J Clin Oncol. 2018 Nov 1;36(31):3101-3109. doi: 10.1200/JCO.2018.77.7326. Epub 2018 Aug 29. Erratum in: J Clin Oncol. 2019 Jan 20;37(3):261. PMID: 30156984.
3: Baltschukat S, Engstler BS, Huang A, Hao HX, Tam A, Wang HQ, Liang J, DiMare MT, Bhang HC, Wang Y, Furet P, Sellers WR, Hofmann F, Schoepfer J, Tiedt R. Capmatinib (INC280) Is Active Against Models of Non-Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation. Clin Cancer Res. 2019 May 15;25(10):3164-3175. doi: 10.1158/1078-0432.CCR-18-2814. Epub 2019 Jan 23. PMID: 30674502.
4: Capmatinib Triggers Responses in NSCLC. Cancer Discov. 2019 Jan;9(1):OF6. doi: 10.1158/2159-8290.CD-NB2018-148. Epub 2018 Nov 14. PMID: 30429129.
5: Esaki T, Hirai F, Makiyama A, Seto T, Bando H, Naito Y, Yoh K, Ishihara K, Kakizume T, Natsume K, Myers A, Doi T. Phase I dose-escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors. Cancer Sci. 2019 Apr;110(4):1340-1351. doi: 10.1111/cas.13956. Epub 2019 Feb 20. PMID: 30724423; PMCID: PMC6447844.
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7: Kim S, Kim TM, Kim DW, Kim S, Kim M, Ahn YO, Keam B, Heo DS. Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib. Cancer Res Treat. 2019 Jul;51(3):951-962. doi: 10.4143/crt.2018.052. Epub 2018 Oct 10. PMID: 30309221; PMCID: PMC6639226.
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9: Capmatinib Could Alter NSCLC Treatment Landscape. Cancer Discov. 2020 Jun;10(6):OF4. doi: 10.1158/2159-8290.CD-NB2020-038. Epub 2020 Apr 29. PMID: 32349974.
10: Burki TK. Preliminary activity of capmatinib with gefitinib in NSCLC. Lancet Oncol. 2018 Oct;19(10):e517. doi: 10.1016/S1470-2045(18)30678-8. Epub 2018 Sep 6. PMID: 30197173.
11: Bang YJ, Su WC, Schuler M, Nam DH, Lim WT, Bauer TM, Azaro A, Poon RTP, Hong D, Lin CC, Akimov M, Ghebremariam S, Zhao S, Giovannini M, Ma B. Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts. Cancer Sci. 2020 Feb;111(2):536-547. doi: 10.1111/cas.14254. Epub 2019 Dec 30. PMID: 31778267; PMCID: PMC7004521.
12: Qin S, Chan SL, Sukeepaisarnjaroen W, Han G, Choo SP, Sriuranpong V, Pan H, Yau T, Guo Y, Chen M, Ren Z, Xu J, Yen CJ, Lin ZZ, Manenti L, Gu Y, Sun Y, Tiedt R, Hao L, Song W, Tanwandee T. A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2019 Dec 11;11:1758835919889001. doi: 10.1177/1758835919889001. Erratum in: Ther Adv Med Oncol. 2020 Mar 12;12:1758835920913426. PMID: 31853265; PMCID: PMC6906348.
13: Going After METex14 in NSCLC. Cancer Discov. 2019 Aug;9(8):OF9. doi: 10.1158/2159-8290.CD-ND2019-006. Epub 2019 Jun 17. PMID: 31209157.
14: Shaker ME, Ashamallah SA, El-Mesery M. The novel c-Met inhibitor capmatinib mitigates diethylnitrosamine acute liver injury in mice. Toxicol Lett. 2016 Nov 2;261:13-25. doi: 10.1016/j.toxlet.2016.08.015. Epub 2016 Aug 21. PMID: 27553677.
15: Bouattour M, Raymond E, Qin S, Cheng AL, Stammberger U, Locatelli G, Faivre S. Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma. Hepatology. 2018 Mar;67(3):1132-1149. doi: 10.1002/hep.29496. Epub 2018 Feb 1. PMID: 28862760; PMCID: PMC5873445.
16: Li H, Li CW, Li X, Ding Q, Guo L, Liu S, Liu C, Lai CC, Hsu JM, Dong Q, Xia W, Hsu JL, Yamaguchi H, Du Y, Lai YJ, Sun X, Koller PB, Ye Q, Hung MC. MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1. Gastroenterology. 2019 May;156(6):1849-1861.e13. doi: 10.1053/j.gastro.2019.01.252. Epub 2019 Jan 31. PMID: 30711629; PMCID: PMC6904924.
17: Saad KM, Shaker ME, Shaaban AA, Abdelrahman RS, Said E. The c-Met inhibitor capmatinib alleviates acetaminophen-induced hepatotoxicity. Int Immunopharmacol. 2020 Apr;81:106292. doi: 10.1016/j.intimp.2020.106292. Epub 2020 Feb 14. PMID: 32062076.
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20: Schuler M, Berardi R, Lim WT, de Jonge M, Bauer TM, Azaro A, Gottfried M, Han JY, Lee DH, Wollner M, Hong DS, Vogel A, Delmonte A, Akimov M, Ghebremariam S, Cui X, Nwana N, Giovannini M, Kim TM. Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial. Ann Oncol. 2020 Mar 30:S0923-7534(20)36380-8. doi: 10.1016/j.annonc.2020.03.293. Epub ahead of print. PMID: 32240796.
INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers. Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment. (source: Clin Cancer Res; 17(22); 7127-38. Â©2011 AACR.)