C-Met/Cancer Survival Protein Platform
(with sound) of c-Met: Promise for cancer therapy
ArQule’s Cancer Survival Protein ("CSP") modulation program, ARQ 650-RP, is designed to modulate survival mechanisms acquired in the evolution of cancer cells and selectively trigger apoptosis. CSPs include cytosolic and nuclear proteins that are inappropriately upregulated in cancer cells and are required for cancer cell survival.
Multiple Roles in Cancer
ArQule's lead CSP modulation product, ARQ 197, is designed to block the activity of a molecule known as c-Met that plays multiple key roles in human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis (the spread of cancer from one part of the body to another). c-Met is inappropriately expressed in almost all types of human cancer, with an established role in tumor development. Activating mutations of c-Met have been increasingly identified in human cancer.
Receptor Tyrosine Kinases
c-Met is a member of a class of enzymes known as receptor tyrosine kinases (“RTKs”) that have emerged with significant potential for anti-cancer therapy. The encouraging results seen with agents such as Imatinib against cancers with the constitutively active Bcr-Abl mutation, as well as Erlotinib, an inhibitor of mutated and over-expressed EGF receptor kinase, have provided an important proof-of-principle that molecularly targeted RTK inhibitors can have an important and broad impact against various cancers.
Broad Potential Applications
c-Met mediates the signals for a variety of physiological processes that have implications for oncogenesis (the initiation of cancer), including migration, invasion, cell proliferation, apoptosis and angiogenesis (the development of new blood vessels). A wide variety of human cancers exhibit constitutively dysregulated c-Met activity, either through over-expression of the c-Met kinase, activating mutations in c-Met, or increased autocrine or paracrine secretion of the c-Met ligand, hepatocyte growth factor/scatter factor (HGF/SF). These alterations have been strongly implicated in tumor progression and metastasis in a variety of cancers, and a high constitutive activation of the c-Met RTK has been correlated with poor clinical prognosis.
We believe the inappropriate expression of c-Met in most cancers and its role in controlling multiple signal transduction pathways involved in tumor growth and metastasis render this enzyme a highly compelling therapeutic target for human cancer. We retain all rights to compounds derived from the ARQ-650RP program, including ARQ 197.