Categorization of protein kinase inhibitors
| Category | Mechanism | Type of binding | Example |
|---|---|---|---|
| Type I | Bind to the ATP-binding site of kinases in their active conformation in their active conformation (DFG-in) | Reversible | Crizotinib (ALK inhibitor) and dasatinib (Src, ABL inhibitor [11]) |
| Type I½ | Binds to the ATP-binding pocket while extending into adjacent regions, stabilizing an intermediate conformation (DFG-in, C-helix out) | Reversible | lapatinib (EGFR, ErbB2 inhibitor [12]) |
| Type II | Binds to the kinases in the inactive conformation (DFG-out) | Reversible | imatinib (ABL inhibitor [13]) and sorafenib (multikinase inhibitor: b-Raf, VEGF, PDGF inhibitor [14]) |
| Type III | Act allosterically by binding to regions outside the ATP-binding site, influencing kinase activity without directly competing for ATP | Reversible | Trametinib, MEK inhibitor [15] |
| Type IV | Substrate-directed inhibitors modulate kinase activity by targeting regions distinct from the ATP-binding site without overlapping with Type III inhibitors | Reversible | mTORC inhibitors, everolimus [10, 16] and sirolimus [17, 18] |
| Type V | Bivalent inhibitors that interact with both the ATP-binding site and additional structural motifs unique to specific kinases | Reversible | Compounds targeting Src family kinases [19] |
| Type VI | Covalently bind to reactive residues, typically cysteines, in the ATP-binding pocket | Mostly irreversible | Afatinib (EGFR, ErbB2, ErbB4 inhibitors [20]) and neratinib (ErbB2, HER2 [21]) |
| Type VII | Nonclassical allosteric inhibitors that target extracellular domains of receptor tyrosine kinases | Mostly 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