Aberrant kinase activity plays a central role in the development and progression of many cancers. Targeting dysregulated kinases is a challenging goal in oncology research. Met kinase, also known as hepatocyte growth factor receptor, is an oncogenic transmembrane receptor tyrosine kinase that once activated mediates a variety of cellular responses including cell growth, migration and invasion, tumor metastasis, and angiogenesis. We discovered a series of 2-amino-3-chloropyridine pyridones as potent inhibitors of Met kinase and selected two compounds for clinical development, one which is highly selective for the Met kinase superfamily and the other which inhibits additional select kinases. JAK2 is another tyrosine kinase that has been implicated in cancer.  A single point mutation in the JH2 pseudokinase domain results in constitutive activation leading to myeloproliferative neoplasms. We discovered imidazopyrrolopyridines as potent and highly selective JAK2 inhibitors, advancing one compound into Phase I human clinical trials.

Met and JAK2 kinase inhibitors for oncology: Two case studies resulting in three development candidates

243rd National Meeting (2012)

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