INCB28060 is a highly potent and orally bioavailable c-Met inhibitor with an IC₅₀ value of 0.13nM[1]. INCB28060 is used to treat adults with metastatic non-small cell lung cancer (NSCLC), including those with NSCLC harboring mutations caused by MET exon 14 skipping[2]. INCB28060 has also demonstrated significant antitumor activity in preclinical models of various cancers, including glioma[3], and intrahepatic cholangiocarcinoma[4]
In vitro, pretreatment with INCB28060 (0–5nM) for 30 minutes to 2 hours in human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes, followed by stimulation with LPS (200ng/ml) for 24 hours, significantly inhibits the expression of adhesion molecules, reduces the release of pro-inflammatory factors, and alleviates the inflammatory response[5]. Pretreatment of HepG2, Huh7, HeLa, and MCF-7 cells with INCB28060 (10μM) for 30 minutes, followed by incubation with different concentrations of doxorubicin (DOX), INCB28060 significantly enhances the apoptotic activity of DOX against cancer cell[6].
In vivo, INCB28060 (10mg/kg) administered orally once daily to a mouse model of NSCLC brain metastasis significantly inhibits the occurrence of brain metastasis and prolongs the survival time of the mice[7]. In a mouse model of diethylnitrosamine-induced acute liver injury, oral administration of INCB28060 (5 mg/kg) significantly reduces the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in the serum. INCB28060 also alleviates hepatocellular ballooning and apoptosis, reduces the production and release of pro-inflammatory cytokines, and decreases the infiltration of inflammatory cells into the liver[8].
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. Clin Cancer Res. 2011 Nov 15;17(22):7127-38.
[2] Bi B, Zhan J, Fan B, et al. The pharmacokinetics of capmatinib and its efficacy in non-small cell lung cancer treatment: a narrative review. Transl Lung Cancer Res. 2025 Jul 31;14(7):2842-2852.
[3] Zuckermann M, He C, Andrews J, et al. Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy. Mol Cancer. 2024 Jun 7;23(1):123.
[4] Gautschi O, Menon R, Bertrand M, et al. Capmatinib and Osimertinib Combination Therapy for EGFR-Mutant Lung Adenocarcinoma. J Thorac Oncol. 2020 Jan;15(1):e13-e15.
[5] Park HS, Abd El-Aty AM, Jeong JH, et al. Capmatinib suppresses LPS-induced interaction between HUVECs and THP-1 monocytes through suppression of inflammatory responses. Biomed J. 2023 Apr;46(2):100534.
[6] Shaker ME, Shaaban AA, El-Shafey MM, et al. The selective c-Met inhibitor capmatinib offsets cisplatin-nephrotoxicity and doxorubicin-cardiotoxicity and improves their anticancer efficacies. Toxicol Appl Pharmacol. 2020 Jul 1;398:115018.
[7] Xia S, Duan W, Xu M, et al. Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET. J Exp Clin Cancer Res. 2024 Apr 3;43(1):103.
[8] Shaker ME, Ashamallah SA, El-Mesery M, et al. The novel c-Met inhibitor capmatinib mitigates diethylnitrosamine acute liver injury in mice. Toxicol Lett. 2016 Nov 2;261:13-25.