Background: The number of drugs in active clinical development or on the market that target the unactivated conformational states of protein kinases is growing and represents a significant portion of kinase research at biopharmaceutical companies. These non-classical kinase inhibitors have a mode of action which may overcome some of the liabilities of classical ATP-site inhibitors that substantially overlap the space that ATP occupies in the activated kinase. Objective: This review will discuss state-of-the-art methods of inhibiting protein kinases by targeting the unactivated conformations of the enzyme with small molecules directed to the ATP binding region. Methods: Biochemical and structural biology publications and public domain crystal structures were evaluated to identify key concepts in drug discovery for unactivated protein kinase inhibitors that target the ATP binding region. Conclusion: The potential for enhanced selectivity, potency and duration of pharmacological action may allow non-classical kinase therapeutics to be used for chronic dosing in non-life-threatening indications. Moreover, by targeting additional conformational space on the kinase protein it is possible that new chemical matter will be discovered such that current intellectual property limitations on traditional ATP-site chemical scaffolds may be circumvented.
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