Several ceritinib resistant mutations following the second l

Several ceritinib-resistant mutations following the second-line treatment of ALK+-NSCLC have been discovered [64]. These mutations include C1156Y, F1174L, and L1152R, which were first observed in crizotinib-resistant tumor samples. The G1202R ceritinib-resistant mutation occurs within the hinge and is in close proximity to the drug; the conversion of the smaller to larger residue may directly impede drug binding. The I1171T and V1180L alectinib-resistant mutations were previously found in crizotinib-resistant tissue samples. Moreover, an additional I1171N alectinib-resistant mutation has been reported. Although clinical experience with lorlatinib is limited, an L1198F resistance mutation has been observed. This residue occurs within the hinge and the larger phenylalanine most likely hinders ALK-lorlatinib complex formation. See Ref. [64] for a list of all of the ALK drug-resistant mutations.
Classification of protein kinase-drug complexes Historically Dar and Shokat defined three ZM 306416 mg of small molecule protein kinase inhibitor: types I, II, and III [65]. The type I inhibitor is a drug that binds within the ATP pocket of the active conformation of the kinase, the type II inhibitor binds to an inactive (usually DFG-out) conformation of the enzyme while the type III inhibitor is an allosteric or a non-ATP competitive antagonist. Allosteric inhibitors bind to a site distinct from the active site [66] and this refers to ligands that bind outside of the ATP-binding pocket of protein kinases. Zuccotto classified type I½ inhibitors as ligands that bind to inactive protein kinases with the DFG-Asp directed inward toward the active site (in contrast to the DFG-Asp out structure) [67]. Gavrin and Saiah subdivided allosteric antagonists into two classes: III and IV [68]. Accordingly, type III inhibitors bind within the cleft between the amino-terminal and carboxyterminal lobes next to, but separate from, the ATP binding pocket while type IV inhibitors bind outside of the cleft. Lamba and Gosh classified bivalent molecules as those antagonists which span two regions of the protein kinase domain as type V inhibitors [69]. To complete this classification we labeled small molecules that form covalent adducts with the target enzyme as type VI inhibitors [44]. We previously divided the type I½ and type II inhibitors into A and B subtypes [44]. The binding of imatinib to Abl is a prototypical type II inhibitor [67]. This drug binds to Abl with the DFG-D out configuration and extends into the back cleft [44] and we classified drugs that extend into the back cleft as type A inhibitors. In contrast, we classified drugs such as bosutinib that bind to the DFG-D out conformation of Abl while not extending into the back cleft as type B inhibitors. Based upon limited data, the practical consequence of this distinction is that type A antagonists bind to the their target kinase with a long residence time when compared with type B inhibitors.
Epilogue In addition to small molecule inhibitors, two monoclonal antibodies (large molecule inhibitors) that directly or indirectly target VEGFR have been approved for the treatment of NSCLC. Ramucirumab binds to VEGFR2 and prevents its activation by ligands, thus inhibiting angiogenesis [70]. The FDA approved ramucirumab in 2014 in combination with docetaxel for the treatment of metastatic NSCLC with disease progression on platinum-based cytotoxic chemotherapy. In 2006, the FDA approved bevacizumab for use as a first-line treatment of metastatic nonsquamous NSCLC in combination with carboplatin/paclitaxel chemotherapy [71]. This drug binds to VEGF-A and prevents the activation of VEGFR thereby inhibiting angiogenesis [72]. The US FDA has approved 29 small molecule drugs that bind directly to the intracellular protein kinase domain (www.brimr.org/PKI/PKIs.htm) and the year that each of these drugs was approved is indicated in Fig. 8. Note that the FDA approved from 2 to 5 new drugs in the years from 2011 to 2015. However, no new small molecule protein kinase antagonists were approved in 2016, but new indications or modifications were reported in 2016 for afatinib, cabozantinib, crizotinib, and palbociclib. Table 4 provides an updated and corrected classification of FDA-approved protein kinase inhibitors based upon the structure of the drug-enzyme complexes as we first reported [44]; the newly added drugs include alectinib, cobimetinib, dabrafenib, ibrutinib, and trametinib. Of the 29 approved drugs, we are lacking X-ray crystal structures of cabozantinib, osimertinib, pazopanib, and regorafenib bound to their drug targets and their consequent structure-based inhibitor classification.