title: Electrophilic fragment-based design of reversible covalent kinase inhibitors.
abstract: Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors. Here, we combine these approaches, starting with a panel of low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which we have previously shown to form reversible covalent bonds with cysteine thiols. Using this strategy, we identify electrophilic fragments with sufficient ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain. Guided by X-ray co-crystal structures, indazole fragment 1 was elaborated to afford 12 (RMM-46), a reversible covalent inhibitor that exhibits high ligand efficiency and selectivity for MSK/RSK-family kinases. At nanomolar concentrations, 12 blocked activation of cellular MSK and RSK, as well as downstream phosphorylation of the critical transcription factor, CREB.
authors.affiliation: Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94158, USA.
authors.forename: Rand M
authors.initials: RM
authors.lastname: Miller
authors.forename: Ville O
authors.initials: VO
authors.lastname: Paavilainen
authors.forename: Shyam
authors.initials: S
authors.lastname: Krishnan
authors.forename: Iana M
authors.initials: IM
authors.lastname: Serafimova
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
mesh_terms: D020106:Acrylamide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003545:Cysteine / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D013438:Sulfhydryl Compounds; D020106:Acrylamide; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D003545:Cysteine
references.citation: EMBO J. 1998 Aug 3;17(15):4426-41
references.pmid: 9687510
references.citation: J Med Chem. 2009 Mar 12;52(5):1231-46
references.pmid: 19203292
references.citation: J Med Chem. 2004 Jul 1;47(14):3463-82
references.pmid: 15214773
references.citation: J Med Chem. 2009 Jan 22;52(2):379-88
references.pmid: 19143567
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9367-72
references.pmid: 10944209
references.citation: J Chem Inf Model. 2011 Jun 27;51(6):1199-204
references.pmid: 21568278
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):12022-7
references.pmid: 9751783
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18281-9
references.pmid: 22988103
references.citation: Nat Rev Cancer. 2009 Jan;9(1):28-39
references.pmid: 19104514
references.citation: J Med Chem. 2011 Jul 28;54(14):5131-43
references.pmid: 21699136
references.citation: J Chem Inf Comput Sci. 2001 May-Jun;41(3):856-64
references.pmid: 11410068
references.citation: J Biol Chem. 2011 Feb 18;286(7):5003-11
references.pmid: 21106525
references.citation: Biochem J. 2005 Apr 15;387(Pt 2):507-17
references.pmid: 15568999
references.citation: Mol Cell Biol. 2002 Apr;22(8):2871-81
references.pmid: 11909979
references.citation: J Biol Chem. 2011 Jan 7;286(1):42-9
references.pmid: 21071437
references.citation: J Proteome Res. 2010 Sep 3;9(9):4433-42
references.pmid: 20681595
references.citation: ChemMedChem. 2012 Dec;7(12):2082-6
references.pmid: 23033251
references.citation: Nat Chem Biol. 2011 Jan;7(1):22-4
references.pmid: 21113170
references.citation: J Med Chem. 2007 Jun 28;50(13):2990-3003
references.pmid: 17523610
references.citation: J Med Chem. 2011 Mar 10;54(5):1347-55
references.pmid: 21322567
references.citation: Nat Chem Biol. 2012 Apr 01;8(5):471-6
references.pmid: 22466421
references.citation: Biochem J. 2012 Jan 1;441(1):347-57
references.pmid: 21970321
references.citation: Nature. 2010 Dec 9;468(7325):790-5
references.pmid: 21085121
references.citation: Leukemia. 2010 May;24(5):1087-90
references.pmid: 20357825