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  • A summary of the drug CDK hydrophobic hydrogen

    2020-11-19

    A summary of the drug-CDK2/6/9 hydrophobic (Φ), hydrogen-bonding (H), and polar-bonding (P) interactions based upon the KLIFS residue numbers is provided in Table 5. The KLIFS system gives comparable residues from different Lu AA 47070 the same value [77], which facilitates comparisons among different protein kinases. The various Hanks domains correspond to those that are listed in Ref. [42]. All of the drugs interact hydrophobically with the Hanks/KLIFS domain I/residue 3, domain II/residues 11 and 15, the back-loop residue 36, domain VII/residue 77, and the x residue immediately before DFG. Residue 3 occurs immediately before the G-rich loop, residue 11 corresponds to CS7 and residue 15 corresponds to CS8, residue 36 corresponds to the conserved valine in the αC-β4 back loop (Sh1), and residue 77 corresponds to CS6 (Table 3). All of the drugs form hydrogen bonds with the third hinge residue. Most of the drugs make hydrophobic contact with (i) the first residue in the G-rich segment, (ii) the side chain of the AxK-lysine, (iii) the gatekeeper phenylalanine, (iv), the penultimate residue as well as the last residue in the catalytic loop, and (v), the DGF-D side chain. The drugs make variable hydrophobic interactions with KLIFS residues 5, 6, and 8 within the G-rich loop, with hinge residues 46 (the first hinge residue), 49 (the forth hinge residue), 51 (the sixth hinge residue), and 52 (the seventh hinge residue). Palbociclib, ribociclib, and alvocidib make polar bonds with DFG-D and abemaciclib and dinaciclib make polar contact with the β3-strand lysine residue. Trilaciclib [[115], [116], [117]], AT7519 [[118], [119], [120], [121]], and voruciclib [[122], [123], [124]] are CDK inhibitors (Fig. 6F–H) that are currently in clinical trials for the treatment of a variety of diseases (Table 4). The structure of SHR6390 [125], which is also in clinical trials, is unknown. Riviciclib is a CDK1/4/9 inhibitor (Fig. 6J) that has been in clinical trials, but in the absence of any new data it is unlikely that his drug will be approved [2]. Unfortunately, we lack X-ray crystal structures of these compounds bound to any protein kinase. All of the drugs listed in Table 4 are orally effective – with the exception of alvocidib and riviciclib, which are given intravenously. See Ref. [6] for the listing of other CDK inhibitors that are or have been in clinical trials, but are no longer considered promising therapeutic agents.
    Epilogue The progression through the cell cycle is an intricate process that involves the precise timing of more than 32,000 phosphorylation and dephosphorylation reactions catalyzed by a network of protein kinases and phosphoprotein phosphatases as determined by mass spectrometry [126]. The mechanism of cell cycle progression has been studied for about 45 years [127]. In a pioneering study, Hartwell et al. used a genetic approach and characterized several cell division cycle (CDC) temperature-sensitive mutants of Saccharomyces cerevisiae whose gene function was required at specific stages of the cell cycle [128]. His initial collection of cell cycle mutants contained changes in what we now recognize as key regulators of the eukaryotic cell cycle. These include CDC28 (CDK1), CDC4 (cell division control protein-4) that facilitates ubiquitylation and thereby destruction of CDK inhibitory proteins (SIC1, CDC6) and is required at G1-S and G2-M transitions as well as components of the anaphase promoting complex or cyclosome (APC/C) involved in promoting cyclin degradation [127]. Nurse similarly used a genetic approach and isolated temperature-sensitive mutants of Schizosaccharomyces pombe that produced smaller size cells than those that divided at the permissive temperature [129]. These wee-1 or small mutants encoded a protein kinase (Wee-1) that catalyzed the phosphorylation and inhibition of CDK1 (Table 1) [127]. Evans and Hunt et al. used a biochemical approach and investigated the regulation of mRNA translation in embryos of the sea urchin Arbacia punctulata [130]. Protein synthesis in young dividing embryos is encoded by stored maternal mRNAs, which correspond to a few abundant proteins whose synthesis is barely, if at all, detectable in the unfertilized egg. One of these proteins, which was named cyclin, was degraded every time that the cells divide. After fertilization, cyclin robustly incorporated [35S]- methionine only to be broken down after mitosis. Moreover, the protein was again labeled during the next cycle only to be degraded yet again at the end of the cycle.