Categorization of protein kinase inhibitors

CategoryMechanismType of binding Example
Type IBind to the ATP-binding site of kinases in their active conformation in their active conformation (DFG-in)ReversibleCrizotinib (ALK inhibitor) and dasatinib (Src, ABL inhibitor [11])
Type I½Binds to the ATP-binding pocket while extending into adjacent regions, stabilizing an intermediate conformation (DFG-in, C-helix out)Reversiblelapatinib (EGFR, ErbB2 inhibitor [12])
Type IIBinds to the kinases in the inactive conformation (DFG-out)Reversibleimatinib (ABL inhibitor [13]) and sorafenib (multikinase inhibitor: b-Raf, VEGF, PDGF inhibitor [14])
Type IIIAct allosterically by binding to regions outside the ATP-binding site, influencing kinase activity without directly competing for ATPReversibleTrametinib, MEK inhibitor [15]
Type IVSubstrate-directed inhibitors modulate kinase activity by targeting regions distinct from the ATP-binding site without overlapping with Type III inhibitorsReversiblemTORC inhibitors, everolimus [10, 16] and sirolimus [17, 18]
Type VBivalent inhibitors that interact with both the ATP-binding site and additional structural motifs unique to specific kinasesReversibleCompounds targeting Src family kinases [19]
Type VICovalently bind to reactive residues, typically cysteines, in the ATP-binding pocketMostly irreversibleAfatinib (EGFR, ErbB2, ErbB4 inhibitors [20]) and neratinib (ErbB2, HER2 [21])
Type VIINonclassical allosteric inhibitors that target extracellular domains of receptor tyrosine kinasesMostly irreversible SSR128129E targeting fibroblast growth factor receptor (FGFR) family [22] and WRG-28 which inhibits the discoidin domain receptors (DDRs) [23]

ALK: anaplastic lymphoma kinase; ABL: Abelson kinase; EGFR: epidermal growth factor receptor; ErbB2: erythroblastic leukemia viral oncogene homolog 2; MEK: mitogen-activated protein kinase kinase 1/2; mTORC: mammalian target of rapamycin complex; WRG-28: N-Ethyl-4-[[(3-oxo-3H-phenoxazin-7-yl)oxy]methyl]-benzenesulfonamide