title: Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: development of chemical probe ML315.
abstract: Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families. Further off-target pharmacological evaluation with ML315, the most selective agent, supports this conclusion.
authors: University of Kansas Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047, USA.
authors: Thomas C
authors: TC
authors: Coombs
authors: Cordelle
authors: C
authors: Tanega
authors: Min
authors: M
authors: Shen
authors: Jenna L
authors: JL
authors: Wang
authors: Douglas S
authors: DS
authors: Auld
authors: Samuel W
authors: SW
authors: Gerritz
authors: Frank J
authors: FJ
authors: Schoenen
authors: Craig J
authors: CJ
authors: Thomas
authors: Jeffrey
authors: J
authors: Aubé
mesh_terms: D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D000097603:Dyrk Kinases; C066780:Clk dual-specificity kinases
references: Biochem J. 2009 Jan 1;417(1):15-27
references: 19061484
references: J Biol Chem. 1998 Oct 2;273(40):25893-902
references: 9748265
references: J Biol Chem. 2004 Jun 4;279(23):24246-54
references: 15010457
references: J Cell Biochem. 2007 Oct 1;102(2):274-9
references: 17583556
references: Exp Cell Res. 1998 Jun 15;241(2):300-8
references: 9637771
references: Biochem J. 1997 Sep 15;326 ( Pt 3):693-700
references: 9307018
references: J Biol Chem. 2010 Apr 23;285(17):13223-32
references: 20167603
references: Nat Struct Mol Biol. 2010 Jun;17(6):718-25
references: 20512148
references: Am J Hum Genet. 2008 May;82(5):1165-70
references: 18405873
references: J Neurosci. 2010 Mar 17;30(11):4004-14
references: 20237271
references: FEBS J. 2009 Nov;276(21):6324-37
references: 19796173
references: Bioorg Med Chem Lett. 2011 May 15;21(10):3152-8
references: 21450467
references: Structure. 2009 Mar 11;17(3):352-62
references: 19278650
references: Cell Mol Life Sci. 2009 Oct;66(20):3235-40
references: 19685005
references: Mol Cell Biol. 1994 Oct;14(10):6954-61
references: 7935412
references: BMC Biochem. 2006 Mar 02;7:7
references: 16512921
references: Biochem Pharmacol. 2008 Dec 1;76(11):1389-94
references: 18599021
references: Exp Cell Res. 1999 Dec 15;253(2):463-73
references: 10585269
references: FASEB J. 2011 Feb;25(2):449-62
references: 21048044
references: Bioorg Med Chem Lett. 2009 Dec 1;19(23):6700-5
references: 19837585
references: Nat Biotechnol. 2004 May;22(5):535-46
references: 15122293
references: Cell Metab. 2010 Jan;11(1):23-34
references: 20074525
references: Mol Cell Biol. 2003 Jun;23(12):4139-49
references: 12773558
references: Retrovirology. 2011 Jun 17;8:47
references: 21682887
references: FEBS J. 2011 Jan;278(2):236-45
references: 21156028
references: J Med Chem. 1972 Oct;15(10):1006-11
references: 5069767
references: FEBS J. 2011 Jan;278(2):246-56
references: 21126318
references: Endocrinology. 2009 May;150(5):2087-97
references: 19116344
references: J Med Chem. 2011 Jun 23;54(12):4172-86
references: 21615147
references: Neurobiol Dis. 2005 Nov;20(2):392-400
references: 16242644
references: Genes Cells. 2008 Mar;13(3):233-44
references: 18298798
references: Arch Biochem Biophys. 2011 Mar 15;507(2):212-8
references: 21185805
references: FEBS J. 2011 Jan;278(2):223-35
references: 21156027
references: Cell Biochem Biophys. 2006;45(3):303-15
references: 16845176
references: Assay Drug Dev Technol. 2009 Dec;7(6):606-14
references: 20059377
references: Chem Biol. 2011 Jan 28;18(1):67-76
references: 21276940
references: Circ Res. 2009 Mar 13;104(5):589-99
references: 19168442
references: Mol Cell Biol. 2002 Sep;22(18):6636-47
references: 12192061
references: Genomics. 1999 May 1;57(3):407-18
references: 10329007
references: Biochem Biophys Res Commun. 1999 Jan 19;254(2):474-9
references: 9918863