![]() In this classification, allosteric inhibitors (non-ATP-competitive) are designated Type III or IV, with Type III being those bound next to the ATP binding site and Type IV away from that site. The additional subcategorization of A or B defines if the inhibitors binding extends into the back cleft (A) or not (B). (4−7) This review follows the inhibitor classification given by Roskoski, (3) namely: Type I are those that bind in and around the ATP binding pocket of an active enzyme, whereas inhibitor Types I1/2 and II bind in and around the ATP binding pocket of an inactive kinase, differing in whether the inactive conformation features the DFG motif in an “- in” or “- out” orientation, respectively. #JIM FINK OPTIONS REVIEW UPDATE#(3−7) For those interested in a detailed description of such properties, we recommend the annual update provided by Roskoski (3) and other excellent revisions published in recent years. Figure 1Ī number of excellent reviews have recently studied the pharmacology and/or mechanism of action of kinase inhibitors. The success of these efforts is evidenced today by the clinical approval of 80+ kinase inhibitors around the world, 66 of them in the USA from 1999 to 2020 ( Figure 1), most of them for cancer treatment, but also against metabolic and autoimmune disorders. (2) Increasing understanding of disease biology has served to validate multiple protein and lipid kinases as drug targets, motivating large investments in drug discovery programs. (1) Due to their integral role in the regulation of intracellular homeostasis and the transduction of extracellular signals, dysregulation of kinase activity is directly involved in numerous progressive disorders, including cancer. Kinases phosphorylate molecules that control complex cellular processes, such as growth, proliferation, differentiation, motility, and apoptosis. Phosphorylation imposes structural changes on the substrate that affect its capacity to associate with other molecules, its subcellular localization, and/or its catalytic activity. Kinases are enzymes that catalyze the transfer of a phosphate group from ATP to specific proteins or small biomolecules, including lipids and carbohydrates. In the last section, we also provide an update on kinase inhibitor drugs approved in 2021. Along with the therapeutic and pharmacological properties of each kinase inhibitor approved across the world until 2020, we provide the synthesis routes originally used during the discovery phase, many of which were only available in patent applications. To complement the published literature on clinical kinase inhibitors, we have prepared a review that recaps this large data set into an accessible format for the medicinal chemistry community. The FDA approved 73 small molecule kinase inhibitor drugs until September 2021, and additional inhibitors were approved by other regulatory agencies during that time. As a result, kinase inhibitors are today one of the most important classes of drugs. The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. ![]()
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