Orally active αvβ3 integrin inhibitor MK-0429 reduces melanoma metastasis

Abstract

Melanoma remains one of the most aggressive types of cancer with a historically low survival rate. The αvβ3 integrin is involved in the progression of malignant melanoma. In the present study, the efficacy of MK-0429, a selective inhibitor of the αvβ3 integrin, was evaluated for its potential in the prevention of melanoma metastasis. Female B6D2F1 mice injected via the tail vein with murine B16F10 melanoma developed lung metastases within ~10 days. In the first experiment, the prevention of lung metastasis was assessed in the model treated with either vehicle, MK-0429 at 100 and 300 mg/kg orally twice daily or cyclophosphamide at 300 mg/kg, i.p. once daily. Study endpoints included determination of the study time period to achieve metastasis in lungs in this model, evaluation of the health effects on the study animals, the total number of lung colonies identified and lung tumor area. Unlike cyclophosphamide, the MK-0429 treatment did not lead to a significant weight reduction in mice. MK-0429 at 100 and 300 mg/kg reduced the number of metastatic tumor colonies by 64 and 57%, respectively, and the high dose also reduced the tumor area by 60% as compared to the vehicle. The second experiment employed B16F10 luciferase-expressing cells to examine the de novo progression of melanoma metastasis over 15 days with bioluminescent imaging of mice treated with MK-0429 at 300 mg/kg as compared to the vehicle. Tumor burden progressively advanced in the lungs of the B16F10-treated animals. However, MK-0429 reduced the progression of ventral and dorsal lung metastases by 22 and 38%, respectively, as compared to the vehicle, by study completion. Quantification of ex vivo tumor burden showed a 30–40% reduction in lung colonies by MK-0429. The two studies collectively demonstrated that MK-0429 was safe and efficacious in significantly decreasing melanoma metastasis in the lungs. The results emphasized the potential of MK-0429 as a novel, therapeutic agent for the prevention of metastatic melanoma.

The role of integrins in melanoma: a review

“…Integrin inhibitors can also be nonproteinaceous small molecules. A 2015 article 65 described an orally active integrin ɑvβ3 small molecule inhibitor called MK‐0429, which showed effectiveness in preventing metastasis in melanoma. The study was performed in female B6D2F1 mice, which were injected with murine syngeneic B16F10 melanoma, known to cause lung metastases.…”

A Penicillin Derivative Exerts an Anti-Metastatic Activity in Melanoma Cells Through the Downregulation of Integrin αvβ3 and Wnt/β-Catenin Pathway

“…2008). It is well documented that increased integrin avb3 expression plays an important role during melanoma progression, promoting cell proliferation, attachment, transendothelial migration and invasion (Felding-Habermann et al, 2002;Kuphal et al, 2005;Pisano et al, 2013;Pickarski et al, 2015). Moreover, the high expression of integrin avb3 in different tumor cells, including osteosarcomas, neuroblastomas, glioblastomas, melanomas, lung carcinomas, and breast cancer, has made it a molecular target for the development of many anticancer drugs which are currently being tested in clinical trials (Zitzmann et al, 2002;Raab-Westphal et al, 2017).…”

Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations

“…The RGD-based compounds cilengitide and a racemic mixture of MK-429 (i.e., containing both MK-429 enantiomers), 36,37,[65][66][67] were characterized by their ability to inhibit the adhesion of HEK-293 cells expressing human αVβ3 to immobilized fibrinogen (IC50) and their ability to induce the exposure of the epitope for mAb AP5 (EC50); thus, higher values for the ratio of EC50 to IC50 indicate that the compound is less able to induce the conformational change. The RGDbased compounds cilengitide and the racemate of MK-429 had IC50s of 29 and 3 nM, EC50s of 48 and 12 nM, and EC50/IC50 ratios of 1.7 and 4.0, respectively (Table 1).…”