TKI258 Dovitinib are well tolerated at doses that achieve clinically meaningful plasma drug concentrations

TKI258 Dovitinib Src inhibition also results in a reduction of cancer progression in several cancer types, thus suggesting a potential clinical usefulness to inhibiting Src. There are several small molecule inhibitors for Src kinase that are undergoing clinical trials after promishing preclinical studies, such as theATP binding competitive inhibitors dasatinib, bosutinib, saracatinib, ponatinib, bafetinib, and the substrate binding site inhibitor Kxo I. Preliminary data suggest that the agents are well tolerated at doses that achieve clinically meaningful plasma drug concentrations. Recent clinical studies with Src inhibitors as single agents or in combination are shown in Table 1.
Dasatinib suppressed invasion and induced cell cycle arrest in HNSCC cells in vitro, affected the GDC-0941 mechanisms of prostate tumor progression, and greatly inhibited the development of liver metastasis in an orthotopic murine model of pancreatic carcinoma. Studies of dasatinib in prostate and colon cancer cell lines showed inhibition of cellular adhesion, migration, and invasion. Breast cancer cell lines belonging to the basal/triple negative subtype were particularly sensitive to dasatinib. Breast cancers within this subgroup express basal cell cytokeratins, with ER, PR and Her2 negative phenotype, and are well known for poor prognosis. Interestingly, in EGFR overexpressing breast cancer cell lines, dasatinib inhibited cell growth, invasion, and angiogenesis, and stimulated apoptosis by activating caspase 8 and 9. Bosutinib showed activity against colon cancer in a murine model and was well tolerated.
In cellular assays, bosutinib treatment resulted in a dose dependent reduction in proliferation, invasion, and migration of breast cancer cells. Furthermore, in a murine model of breast carcinoma, bosutinib inhibited tumor growth and significantly reduced the number of liver, spleen, and lung metastases. Clinical trials with bosutinib for breast cancer, other solid tumors, and leukemia are ongoing. Saracatinib is another ATP competitive inhibitor of SFKs, with activity against ABL and activated mutant forms of EGFR. In a panel of 13 human cancer cell lines treated with saracatinib, there was growth inhibition in four different cell lines and inhibitory effects on migration and invasion.
In a recent phase II trial with dasatinib as a first line of treatment for metastatic NSCLC several patients had prolonged stable disease and one patient had a near complete response that persisted 2 years after the start of therapy, suggesting that there was a subset of patients with NSCLC who benefited from Src inhibition. Another independent phase I/II study in NSCLC using the combination of Src and EGFR inhibitors also demonstrated clinical responses. These observations further validate the preclinical findings that suggest there is cooperation between EGFR kinase activity and Src in NSCLC. In a phase II trial in 2008, Yu et al. demonstrated that dasatinib improves the overall survival in castration resistant prostate cancer. Based on promising results from phase I/II clinical trials of combination treatment with dasatinib and docetaxel in prostate cancer patients, this combination is now being tested in a phase III clinical trials. M475271 is an oral inhibitor of Src a