Chemistry & Biology
Novel Specific CLK Inhibitors
structures of MEK1 binary and ternary complexes with nucleotides and inhib-
of alternative splicing by a newly developed inhibitor of Clks. J. Biol. Chem.
itors. Biochemistry 48, 2661–2674.
279, 24246–24254.
Gui, J.F., Lane, W.S., and Fu, X.D. (1994). A serine kinase regulates intracellular
Murshudov, G.N., Vagin, A.A., and Dodson, E.J. (1997). Refinement of macro-
molecular structures by the maximum-likelihood method. Acta Crystallogr. D
Biol. Crystallogr. 53, 240–255.
localization of splicing factors in the cell cycle. Nature 369, 678–682.
Harper, S.J., and Bates, D.O. (2008). VEGF-A splicing: the key to anti-angio-
genic therapeutics? Nat. Rev. Cancer 8, 880–887.
Nowak, D.G., Woolard, J., Amin, E.M., Konopatskaya, O., Saleem, M.A.,
Churchill, A.J., Ladomery, M.R., Harper, S.J., and Bates, D.O. (2008).
Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regu-
lated by splicing and growth factors. J. Cell Sci. 121, 3487–3495.
Hernandes, M.Z., Cavalcanti, S.M., Moreira, D.R., de Azevedo Junior, W.F.,
and Leite, A.C. (2010). Halogen atoms in the modern medicinal chemistry: hints
for the drug design. Curr. Drug Targets 11, 303–314.
Huber, K., Schemies, J., Uciechowska, U., Wagner, J.M., Rumpf, T., Lewrick,
F., Su¨ ss, R., Sippl, W., Jung, M., and Bracher, F. (2010a). Novel 3-arylidenein-
dolin-2-ones as inhibitors of NAD+ -dependent histone deacetylases (sirtuins).
J. Med. Chem. 53, 1383–1386.
Painter, J., and Merritt, E.A. (2006). Optimal description of a protein structure in
terms of multiple groups undergoing TLS motion. Acta Crystallogr. D Biol.
Crystallogr. 62, 439–450.
Pajares, M.J., Ezponda, T., Catena, R., Calvo, A., Pio, R., and Montuenga, L.M.
(2007). Alternative splicing: an emerging topic in molecular and clinical
oncology. Lancet Oncol. 8, 349–357.
Huber, K., Kast, O., and Bracher, F. (2010b).
A versatile synthesis
of 3-substituted 4-cyano-1,2,3,4-tetrahydro-1-oxo-b-carbolines. Synthesis,
3849–3854.
Perrakis, A., Morris, R., and Lamzin, V.S. (1999). Automated protein model
building combined with iterative structure refinement. Nat. Struct. Biol. 6,
458–463.
Jacobs, M.D., Black, J., Futer, O., Swenson, L., Hare, B., Fleming, M., and
Saxena, K. (2005). Pim-1 ligand-bound structures reveal the mechanism of
serine/threonine kinase inhibition by LY294002. J. Biol. Chem. 280, 13728–
13734.
Pogacic, V., Bullock, A.N., Fedorov, O., Filippakopoulos, P., Gasser, C.,
Biondi, A., Meyer-Monard, S., Knapp, S., and Schwaller, J. (2007). Structural
analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with
in vitro antileukemic activity. Cancer Res. 67, 6916–6924.
Jiang, K., Patel, N.A., Watson, J.E., Apostolatos, H., Kleiman, E., Hanson, O.,
Hagiwara, M., and Cooper, D.R. (2009). Akt2 regulation of Cdc2-like kinases
(Clk/Sty), serine/arginine-rich (SR) protein phosphorylation, and insulin-
induced alternative splicing of PKCbetaII messenger ribonucleic acid.
Endocrinology 150, 2087–2097.
Prasad, J., Colwill, K., Pawson, T., and Manley, J.L. (1999). The protein kinase
Clk/Sty directly modulates SR protein activity: both hyper- and hypophosphor-
ylation inhibit splicing. Mol. Cell. Biol. 19, 6991–7000.
Karaman, M.W., Herrgard, S., Treiber, D.K., Gallant, P., Atteridge, C.E.,
Campbell, B.T., Chan, K.W., Ciceri, P., Davis, M.I., Edeen, P.T., et al. (2008).
A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol. 26,
127–132.
Ritchie, D.B., Schellenberg, M.J., and MacMillan, A.M. (2009). Spliceosome
structure: piece by piece. Biochim. Biophys. Acta 1789, 624–633.
Rodgers, J.T., Haas, W., Gygi, S.P., and Puigserver, P. (2010). Cdc2-like
kinase 2 is an insulin-regulated suppressor of hepatic gluconeogenesis. Cell
Metab. 11, 23–34.
Karlas, A., Machuy, N., Shin, Y., Pleissner, K.P., Artarini, A., Heuer, D., Becker,
D., Khalil, H., Ogilvie, L.A., Hess, S., et al. (2010). Genome-wide RNAi screen
identifies human host factors crucial for influenza virus replication. Nature
463, 818–822.
Sheldrick, G.M. (2008). A short history of SHELX. Acta Crystallogr. A 64,
112–122.
Larsen, L.K., Moore, R.E., and Patterson, G.M. (1994). beta-Carbolines from
Shi, J., Zhang, T., Zhou, C., Chohan, M.O., Gu, X., Wegiel, J., Zhou, J., Hwang,
Y.W., Iqbal, K., Grundke-Iqbal, I., et al. (2008). Increased dosage of Dyrk1A
alters alternative splicing factor (ASF)-regulated alternative splicing of tau in
Down syndrome. J. Biol. Chem. 283, 28660–28669.
the blue-green alga Dichothrix baueriana. J. Nat. Prod. 57, 419–421.
Leslie, A.G.W., and Powell, H. (2007). MOSFLM (Cambridge: MRC Laboratory
of Molecular Biology).
Lin, R., Connolly, P.J., Huang, S., Wetter, S.K., Lu, Y., Murray, W.V., Emanuel,
S.L., Gruninger, R.H., Fuentes-Pesquera, A.R., Rugg, C.A., et al. (2005). 1-
Acyl-1H-[1,2,4]triazole-3,5-diamine analogues as novel and potent anticancer
cyclin-dependent kinase inhibitors: synthesis and evaluation of biological
activities. J. Med. Chem. 48, 4208–4211.
Smyth, L.A., and Collins, I. (2009). Measuring and interpreting the selectivity of
protein kinase inhibitors. J. Chem. Biol. 2, 131–151.
Stamm, S. (2008). Regulation of alternative splicing by reversible protein phos-
phorylation. J. Biol. Chem. 283, 1223–1227.
Szotowski, B., Goldin-Lang, P., Antoniak, S., Bogdanov, V.Y., Pathirana, D.,
Pauschinger, M., Dorner, A., Kuehl, U., Coupland, S., Nemerson, Y., et al.
(2005). Alterations in myocardial tissue factor expression and cellular localiza-
tion in dilated cardiomyopathy. J. Am. Coll. Cardiol. 45, 1081–1089.
Long, J.C., and Caceres, J.F. (2009). The SR protein family of splicing factors:
master regulators of gene expression. Biochem. J. 417, 15–27.
Manley, P.W., Drueckes, P., Fendrich, G., Furet, P., Liebetanz, J., Martiny-
Baron, G., Mestan, J., Trappe, J., Wartmann, M., and Fabbro, D. (2010).
Extended kinase profile and properties of the protein kinase inhibitor nilotinib.
Biochim. Biophys. Acta 1804, 445–453.
Tardos, J.G., Eisenreich, A., Deikus, G., Bechhofer, D.H., Chandradas, S.,
Zafar, U., Rauch, U., and Bogdanov, V.Y. (2008). SR proteins ASF/SF2 and
SRp55 participate in tissue factor biosynthesis in human monocytic cells.
J. Thromb. Haemost. 6, 877–884.
McCoy, A.J., Grosse-Kunstleve, R.W., Storoni, L.C., and Read, R.J. (2005).
Likelihood-enhanced fast translation functions. Acta Crystallogr.
D Biol.
Voth, A.R., and Ho, P.S. (2007). The role of halogen bonding in inhibitor recog-
Crystallogr. 61, 458–464.
nition and binding by protein kinases. Curr. Top. Med. Chem. 7, 1336–1348.
Morphy, R. (2010). Selectively nonselective kinase inhibition: striking the right
Wahl, M.C., Will, C.L., and Luhrmann, R. (2009). The spliceosome: design prin-
balance. J. Med. Chem. 53, 1413–1437.
ciples of a dynamic RNP machine. Cell 136, 701–718.
Mott, B.T., Tanega, C., Shen, M., Maloney, D.J., Shinn, P., Leister, W.,
Marugan, J.J., Inglese, J., Austin, C.P., Misteli, T., et al. (2009). Evaluation of
substituted 6-arylquinazolin-4-amines as potent and selective inhibitors of
cdc2-like kinases (Clk). Bioorg. Med. Chem. Lett. 19, 6700–6705.
Ward, A.J., and Cooper, T.A. (2010). The pathobiology of splicing. J. Pathol.
220, 152–163.
Yamaguchi, H., Miwa, Y., Kasa, M., Kitano, K., Amano, M., Kaibuchi, K., and
Hakoshima, T. (2006). Structural basis for induced-fit binding of Rho-kinase
to the inhibitor Y-27632. J. Biochem. 140, 305–311.
Muraki, M., Ohkawara, B., Hosoya, T., Onogi, H., Koizumi, J., Koizumi, T.,
Sumi, K., Yomoda, J., Murray, M.V., Kimura, H., et al. (2004). Manipulation
76 Chemistry & Biology 18, 67–76, January 28, 2011 ª2011 Elsevier Ltd All rights reserved