From Type I to Type II: Design, Synthesis, and Characterization of Potent Pyrazin-2-ones as DFG-Out Inhibitors of PDGFRβ.

Reversible protein kinase inhibitors that bind in the ATP cleft can be classified as type I or type II binders. Of these, type I inhibitors address the active form, whereas type II inhibitors typically lock the kinase in an inactive form. At the molecular level, the conformation of the flexible activation loop holding the key DFG motif controls access to the ATP site, thereby determining an active or inactive kinase state.