A single residue in the ATP binding pocket of protein kinases—termed the gatekeeper—has been shown to control sensitivity to a wide range of small molecule inhibitors (Chem. Biol. 2004, 11, 691; Chem. Biol. 1999, 6, 671). Kinases that possess a small side chain at this position (Thr, Ala, or Gly) are readily targeted by structurally diverse classes of inhibitors, whereas kinases that possess a larger residue at this position are broadly resistant. ...
