Targeted covalent inhibitor

Targeted covalent inhibitors (TCIs) or Targeted covalent drugs are rationally designed inhibitors that bind and then bond to their target proteins. These inhibitors possess a bond-forming functional group of low chemical reactivity that, following binding to the target protein, is positioned to react rapidly with a specific nucleophilic residue at the target site and form a bond (Singh, Petter, Baillie, & Whitty, 2011a).

Over the last 100 years covalent drugs have made a major impact on human health and have been highly successful drugs for the pharmaceutical industry (Robertson, 2005)). These inhibitors react with their target proteins to form a covalent complex in which the protein has lost its function. The majority of these successful drugs, which include penicillin, omeprazole, clopidogrel, and aspirin were discovered through serendipity in phenotypic screens (Potashman & Duggan, 2009).

For the past 20 years key changes in screening approaches, along with safety concerns, have made pharma reluctant to pursue covalent inhibitors in a systematic way (Liebler & Guengerich, 2005)(Park et al., 2011).

Recently, there has been considerable attention to using rational drug design to create highly selective covalent inhibitors called targeted covalent inhibitors (Singh, Petter, & Kluge, 2010). The first published example of a targeted covalent drug was for the EGFR kinase (Singh et al., 1997) (Fry et al., 1998) but this has now broadened to other kinases (Singh et al., 2010) (Cohen, Zhang, Shokat, & Taunton, 2005) and other protein families (Hagel et al., 2011; Nacht et al., 2010) (Ostrem, Peters, Sos, Wells, & Shokat, 2013).

Covalent bonding can lead to potencies and ligand efficiencies that are either exceptionally high or, for irreversible covalent interactions, even essentially infinite. Covalent bonding thus allows high potency to be routinely achieved in compounds of low molecular mass, along with all the beneficial pharmaceutical properties that are associated with small size (Smith, Zhang, Leach, & Houk, 2009)

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