Synthesis and evaluation of new dual inhibitors for c-Met and Wnt

Abstract

The tyrosine kinase receptor c-Met is seen upregulated in several types of cancers and is associated with metastasis and a poor prognosis of the disease. In general for cancer drugs there is seen a development of resistance after use over time. For c-Met, the signal pathway Wnt is seen upregulated when resistance to c-Met therapy has developed. Instead of inhibiting each target separately, we have developed dual c-Met and Wnt inhibitors due to structural resemblance between selective c-Met and Wnt inhibitors. The benefit of synthesizing dual inhibitors are that the inhibitors have their own pharmacological profile, pharmacokinetics and possible fewer side effects and drug interactions. The inhibitors are synthesized from pyridazinone and triazolopyridazine intermediates linked to oxazolopyridine or oxadizole ring systems via nucleophilic substitution reactions. The inhibitors synthesized were tested in c-Met and Wnt assays.