Kinases

Unregulated activation of protein kinases often results in diseases, including cancer and autoimmune disorders. Thus, kinases provide tumor-specific targets for drugs that may work as stand-alone therapies or enhance traditional therapy with minimal added side effects. Kinase inhibition for cancer treatment has been validated by the success of few FDA-approved small molecule and antibody therapies. With more than 500 distinct protein kinases identified, kinases are a rich area for therapeutic drug development.

There are several reasons why kinases are considered today among the most promising classes of drug targets. First, with approximately 518 kinases encoded in the human genome, almost all signaling pathways are wired through kinese mediated phospho-transfer cascade. This supports the notion that the inhibition of kinase activity can elicit a real physiological response. This notion has gained support with the success of the first approved kinase inhibitor, Imatinib for the treatment ofCML (Chronic Myeloid Leukimia), as well as with subsequent approvals of additional kinase inhibitors. Second, despite a high degree of conservation in the kinase ATP binding site, highly selective, small molecules with desired pharmaceutical properties have been developed. Third, as evident in the collected clinical experience, inhibition of kinase activity in normal cells can be tolerated. This presents a therapeutic window for the selective killing of tumor cells, offering more favorable side effect profiles than conventional cytotoxic chemotherapy. Fourth, drugs such as Imatinib have had high profile success, exhibiting 97% response rate in CML, with 98% of patients staying free of the disease even after 7 years, and up to 80% response rates in the chronic phase of CML.

Despite the encouraging status of the field, it  faces significant challenges due to drug resistance, lack of inhibitor selectivity, lack of inhibitor efficacy, and difficulty in drug target validation in some disease settings.