title: Composition and applications of focus libraries to phenotypic assays.
abstract: The wealth of bioactivity information now available on low-molecular weight compounds has enabled a paradigm shift in chemical biology and early phase drug discovery efforts. Traditionally chemical libraries have been most commonly employed in screening approaches where a bioassay is used to characterize a chemical library in a random search for active samples. However, robust curating of bioassay data, establishment of ontologies enabling mining of large chemical biology datasets, and a wealth of public chemical biology information has made possible the establishment of highly annotated compound collections. Such annotated chemical libraries can now be used to build a pathway/target hypothesis and have led to a new view where chemical libraries are used to characterize a bioassay. In this article we discuss the types of compounds in these annotated libraries composed of tools, probes, and drugs. As well, we provide rationale and a few examples for how such libraries can enable phenotypic/forward chemical genomic approaches. As with any approach, there are several pitfalls that need to be considered and we also outline some strategies to avoid these.
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research Cambridge, MA, USA.
authors.forename: Anne Mai
authors.initials: AM
authors.lastname: Wassermann
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research Cambridge, MA, USA.
authors.forename: Luiz M
authors.initials: LM
authors.lastname: Camargo
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research Cambridge, MA, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Auld
keywords: chemical libraries; chemical probes; focused library; high-throughput screening; phenotypic assays
references.citation: Toxicol Sci. 2012 Dec;130(2):217-28
references.pmid: 22790972
references.citation: Sci Transl Med. 2011 Apr 27;3(80):80ps16
references.pmid: 21525397
references.citation: Hum Mutat. 2011 May;32(5):564-7
references.pmid: 21472891
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D142-8
references.pmid: 19843607
references.citation: Nat Rev Drug Discov. 2004 Apr;3(4):353-9
references.pmid: 15060530
references.citation: Bioinformatics. 2008 Nov 1;24(21):2518-25
references.pmid: 18784118
references.citation: Nature. 2012 Jun 10;486(7403):361-7
references.pmid: 22722194
references.citation: Curr Opin Chem Biol. 2010 Jun;14(3):315-24
references.pmid: 20417149
references.citation: J Med Chem. 1997 Apr 11;40(8):1219-29
references.pmid: 9111296
references.citation: J Biomol Screen. 2014 Jun;19(5):651-60
references.pmid: 24246376
references.citation: J Cheminform. 2013 Jan 24;5(1):7
references.pmid: 23343401
references.citation: Mol Pharmacol. 1987 Jul;32(1):133-9
references.pmid: 3600614
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D1075-82
references.pmid: 24198245
references.citation: Methods Mol Biol. 2013;947:343-74
references.pmid: 23138916
references.citation: J Med Chem. 2008 Apr 24;51(8):2363-71
references.pmid: 18363325
references.citation: J Med Chem. 2010 Apr 8;53(7):2719-40
references.pmid: 20131845
references.citation: Pharmacol Rev. 2011 Sep;63(3):750-71
references.pmid: 21737530
references.citation: Nat Struct Mol Biol. 2004 Dec;11(12):1192-7
references.pmid: 15543157
references.citation: J Comb Chem. 2008 Jan-Feb;10(1):3-19
references.pmid: 18067268
references.citation: Assay Drug Dev Technol. 2003 Aug;1(4):579-92
references.pmid: 15090254
references.citation: J Chem Inf Model. 2006 Mar-Apr;46(2):512-24
references.pmid: 16562979
references.citation: Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):5048-53
references.pmid: 24707051
references.citation: Chem Biol. 2012 Aug 24;19(8):1060-72
references.pmid: 22921073
references.citation: Nat Rev Cancer. 2007 Jan;7(1):54-60
references.pmid: 17186018
references.citation: AAPS J. 2006 May 26;8(2):E371-82
references.pmid: 16796388
references.citation: Comb Chem High Throughput Screen. 2011 Jul;14(6):521-31
references.pmid: 21521154
references.citation: Drug Discov Today. 2006 Mar;11(5-6):261-6
references.pmid: 16580603
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D199-205
references.pmid: 24214961
references.citation: Nat Chem Biol. 2010 Mar;6(3):159-161
references.pmid: 20154659
references.citation: Nat Rev Drug Discov. 2009 Dec;8(12):959-68
references.pmid: 19949401
references.citation: J Chem Inf Model. 2009 Apr;49(4):1049-62
references.pmid: 19301874
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D1091-7
references.pmid: 24203711
references.citation: Chem Biol. 2011 Oct 28;18(10):1273-83
references.pmid: 22035796
references.citation: Biochem J. 2007 Dec 15;408(3):297-315
references.pmid: 17850214
references.citation: Mol Nutr Food Res. 2010 Feb;54(2):218-27
references.pmid: 20041446
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D530-5
references.pmid: 23161678
references.citation: Nat Chem Biol. 2008 Nov;4(11):682-90
references.pmid: 18936753
references.citation: Nat Rev Drug Discov. 2011 Jun 24;10(7):507-19
references.pmid: 21701501
references.citation: Genome Biol. 2006;7(10):R93
references.pmid: 17044931
references.citation: Drug Discov Today. 2013 Jul;18(13-14):674-80
references.pmid: 23454345
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D52-7
references.pmid: 21115458
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2665-74
references.pmid: 22949700
references.citation: Chem Biol. 2003 Sep;10(9):881-92
references.pmid: 14522058
references.citation: Mol Biosyst. 2014 Feb;10(2):251-7
references.pmid: 24257700
references.citation: ACS Chem Biol. 2012 Aug 17;7(8):1399-409
references.pmid: 22594495
references.citation: ACS Chem Biol. 2013 May 17;8(5):1009-17
references.pmid: 23485150
references.citation: J Comb Chem. 2006 Sep-Oct;8(5):597-635
references.pmid: 16961395
references.citation: Science. 1996 Apr 19;272(5260):408-11
references.pmid: 8602529
references.citation: J Biomol Screen. 2014 Jun;19(5):791-802
references.pmid: 24518063
references.citation: J Biomol Screen. 2014 Jun;19(5):614-27
references.pmid: 24441647
references.citation: Curr Top Med Chem. 2004;4(7):653-69
references.pmid: 15032680
references.citation: Clin Pharmacol Ther. 2013 Sep;94(3):407-11
references.pmid: 23756372
references.citation: Curr Top Med Chem. 2012;12(17):1896-902
references.pmid: 23116469
references.citation: J Biotechnol. 2005 Sep 29;119(3):219-44
references.pmid: 16005536
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8
references.pmid: 16864780
references.citation: Nat Chem Biol. 2011 Jul 10;7(8):566-74
references.pmid: 21743462
references.citation: Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547-51
references.pmid: 1319065
references.citation: Science. 2011 Dec 2;334(6060):1278-83
references.pmid: 22052977
references.citation: Future Med Chem. 2011 Apr;3(6):751-66
references.pmid: 21554080
references.citation: Exp Cell Res. 1972 Sep;74(1):61-6
references.pmid: 4672477
references.citation: Nature. 2012 Dec 13;492(7428):215-20
references.pmid: 23235874
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Drug Discov Today. 2013 May;18(9-10):495-501
references.pmid: 23340113
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D800-6
references.pmid: 21045057
references.citation: ACS Chem Biol. 2014 Mar 21;9(3):777-84
references.pmid: 24397822
references.citation: Curr Pharm Des. 2001 May;7(7):567-97
references.pmid: 11375769
references.citation: PLoS One. 2013;8(3):e57888
references.pmid: 23505445
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D1100-7
references.pmid: 21948594
references.citation: Leukemia. 2002 Apr;16(4):520-6
references.pmid: 11960328
references.citation: J Med Chem. 2012 Jun 14;55(11):5165-73
references.pmid: 22643060
references.citation: Comb Chem High Throughput Screen. 2004 Aug;7(5):495-510
references.pmid: 15320714
references.citation: Angew Chem Int Ed Engl. 2008;47(1):48-56
references.pmid: 18080276
references.citation: Assay Drug Dev Technol. 2008 Aug;6(4):505-18
references.pmid: 18699726
references.citation: Chem Res Toxicol. 2012 Jul 16;25(7):1287-302
references.pmid: 22519603
references.citation: J Med Chem. 1988 Dec;31(12):2235-46
references.pmid: 2848124
references.citation: Drug Discov Today. 2011 Feb;16(3-4):99-106
references.pmid: 21093609
references.citation: Chem Biol. 2010 Jun 25;17(6):561-77
references.pmid: 20609406
references.citation: J Med Chem. 1979 Jan;22(1):1-7
references.pmid: 34039
references.citation: PLoS One. 2013 Apr 16;8(4):e61007
references.pmid: 23613770
references.citation: Nat Chem Biol. 2007 Aug;3(8):466-79
references.pmid: 17637779
references.citation: Drug Discov Today. 2012 Jul;17(13-14):718-26
references.pmid: 22515962
references.citation: Expert Rev Clin Pharmacol. 2013 Jan;6(1):41-7
references.pmid: 23272792
references.citation: Chembiochem. 2013 Feb 11;14(3):295-300
references.pmid: 23364933
references.citation: J Med Chem. 2007 May 17;50(10):2385-90
references.pmid: 17447748
references.citation: Nat Chem Biol. 2009 Jul;5(7):479-83
references.pmid: 19483698
references.citation: Nat Rev Drug Discov. 2014 Mar;13(3):179-96
references.pmid: 24577400
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):6805-10
references.pmid: 21415367