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  • br Acknowledgments br Introduction to the somatic mitotic ce


    Introduction to the somatic mitotic cell cycle
    Cell cycle dysregulation and cancer
    Structures of the cyclin-dependent protein kinases
    Structure of the CDK hydrophobic skeletons
    Classification of protein kinase-drug complexes Dar and Shokat defined three 5-aminosalicylic acid of protein kinase inhibitors and labeled them types I, II, and III [68]. Type I inhibitors bind in the adenine-binding pocket of an active protein kinase; type II inhibitors bind to an inactive protein kinase with the activation segment DFG-D pointing away from the active site (DFG-Dout); type III inhibitors bind to an allosteric site that is separate from the adenine-binding pocket. Zuccotto subsequently defined type I½ inhibitors as drugs that bind to an inactive protein kinase with the activation segment DFG-D directed inward (DFG-Din) toward the active site (in contrast to the DFG-Dout conformation) [69]. A dormant protein kinase may display a closed activation segment, an αCout conformation, a nonlinear or broken regulatory spine, or various combinations thereof. Gavrin and Saiah then divided allosteric inhibitors into two types: III and IV [70]. Type III inhibitors bind within the cleft between the small and large lobes and next to, but independent of, the ATP binding site while type IV inhibitors bind outside of the cleft. Moreover, Lamba and Gosh described bivalent antagonists as those inhibitors that span two distinct parts of the protein kinase domain as type V inhibitors [71]. For example, a drug that bound to the adenine-binding pocket as well as the peptide substrate site would be classified as a type V inhibitor. To complete this classification, we labeled drugs that bind covalently with the target enzyme as type VI inhibitors [46]. For example, afatinib is a type VI covalent FDA-approved inhibitor of mutant EGFR that is used for the treatment of NSCLC. Mechanistically, this compound binds initially to an active EGFR conformation (like a type I inhibitor) and then the C797 –SH group of EGFR attacks the drug to form an irreversible covalent adduct (PDB ID: 4G5J) [53]. Owing to the variation of inactive protein kinase conformations as compared with the conserved active conformation, it was suggested that type II inhibitors would be more selective than type I inhibitors, which bind to the canonical active conformation. The results of Vijayan et al. support this suggestion [72] while those of Kwarcinski et al. and Zhao et al. do not [73,74]. By definition, type III allosteric inhibitors bind next to the adenine binding pocket [70]. Owing to the greater variability of this region when compared with the adenine-binding site, type III inhibitors have the potential to possess greater selectivity than type I, I½, or II inhibitors. Moreover, Kwarcinski et al. propose that inhibitors that bind to the αCout conformation (type I½ inhibitors) may be more selective than type I and II antagonists [73]. FDA-approved αCout inhibitors include abemaciclib, palbociclib, and ribociclib (all CKD4/6 antagonists). However, Kwarcinski et al. proposed that not all protein kinases are able to assume the αCout conformation while they suggest that all protein kinases are able to adopt the DFG-Dout conformation [73]. We divided the type I½ and type II inhibitors into A and B subtypes [53]. Drugs that extend into the back cleft are classified as type A inhibitors. In contrast, drugs that do not extend into the back cleft as are classified as type B inhibitors. Based upon incomplete data, the potential significance of this difference is that type A inhibitors bind to their target enzyme with longer residence times when compared with type B inhibitors [53]. Imatinib is an FDA-approved drug for the treatment of chronic myelogenous leukemia and several other disorders that is a type IIA inhibitor of BCR-Abl that extends far into the back cleft. Bosutinib is an FDA-approved drug for the treatment of chronic myelogenous leukemia that is a type IIB inhibitor of BCL-Abl that does not extend into the back cleft [53].