Kinase Inhibitors I.pdf

708 Molecular Cell 58,May 21,2015 2015 Elsevier Inc.DOI http:/dx.doi.org/10.1016/j.molcel.2015.05.001SnapShot:Kinase Inhibitors IJinhua Wang1,2 and Nathanael S.Gray1,21Department of Cancer Biology,Dana-Farber Cancer Institute,Boston,MA 02215,USA2Department of Biological Chemistry&Molecular Pharmacology,Harvard Medical School,Boston,MA 02115,USAKinase nameTool compound IC50 Known off targetsOther compoundsCAS numberPubMed IDAKTMK2206Akt1:8 nM;Akt2:12 nM;Akt3:65 nMGSK690693(ATP-competitive)1032349-93-1,1032350-13-2(HCl salt)20571069AKT1A-674563Akt1:11 nM(Ki)PKA,CDK2 552325-73-215956255p70S6KPF-4708671160 nMMSK11255517-76-020704563PDK1GSK23344702.5 nM1227911-45-621341675PKCSotrastaurinPKC:0.22 nM(Ki);PKC:0.64 nM(Ki);PKC:0.95 nM(Ki);PKC:1.8 nM(Ki);PKC:2.1 nM(Ki);PKC:3.2 nM(Ki)Go 6983425637-18-919491325PKCEnzastaurin6 nMPKC,g,170364-57-516103100PKCCompound 4123 nMPKC1613717-26-225000588ROCK1/2GSK269962AROCK1:1.6 nM;ROCK2:4 nMMSK1,RSK1GSK429286A850664-21-017018693RSKBI-D1870RSK1:31 nM;RSK2:24 nM;RSK3:18 nM;RSK4:15 nMMST2FMK(covalent)501437-28-117040210RSK2BIX 025651.1 nMLRRK2,PRKD1/2/3,RET1311367-27-722056746SGK1/2GSK650394SGK1:62 nM;SGK2:103 nMEMD638683890842-28-118794135ATMKU-600196.3 nMPI3K(p110/p85),PI3K(p120g),and PI3K(p110/p85)KU-55933,CP-466722925701-49-119808981ATRVE-82113 nM(Ki)AZ201232410-49-921490603FRAPAZD20142.8 nMINK128,Torin2,Torin1,KU-0063794,WYE-354,AZD80551009298-59-223375793FRAPRapamycin 0.1 nMEverolimus,Ridaforolimus 53123-88-917350953PDHKVER-246608PDHK1:35 nM;PDHK2:84 nM;PDHK3:40 nM;PDHK4:91 nMAZD754525404640CaMK2KN-93370 nM(Ki)KN-62,Scios 15b,SMP-1141188890-40-5,1188890-41-6(phos-phate salt)1662507CHK1PF-477736Chk1:0.49 nM;Chk2:47 nMVEGFR2,FMS,YESSCH900776,LY2603618,CHIR-124952021-60-218723486CHK2CCT241533Chk2:3 nM;Chk1:190 nMPHK,MARK31262849-73-921239475MAPKAPK2PF36440225.2 nMMAPKAPK3,MAPKAPK51276121-88-020237073MELKOTSSP1670.41 nMmultipleMELK-T11431697-89-023283305MLCKMLCK inhibitor peptide 1850 nM224579-74-210072688NuaK1/2WZ4003NUAK1:20 nM;NUAK2:100 nMHTH01-0151214265-58-324171924PIM1/2/3AZD1208Pim1:0.4 nM;Pim2:5 nM;Pim3:1.9 nM CDK7,MAPK15LGB321,CX-62581204144-28-424363397PKD1/2/3CRT 0066101PKD1:1 nM;PKD2:2.5 nM;PKD3:2 nMkb NB 142-70,BPKDi956123-34-5,1290629-45-6(HCl Salt)20442301SIK1/2/3HG-9-91-01SIK1:0.92 nM;SIK2:6.6 nM;SIK3:9.6 nMNUAK2,Src,Yes,EphA41456858-58-423033494CK1PF-4800567CK1:32 nM;CK1:711 nMEGFRD4476,PF-6704621188296-52-719458106CDK1/2BMS-265246CDK1:6 nM;CDK2:9 nMCDK4R-547582315-72-812824044CDK4/6PD0332991CDK4:9 nM;CDK6:15 nM571190-30-215542782CDK7THZ1 3.2 nMBMS1811604810-83-4 25043025CDK9NVP-20.5 nMNVP-1,SNS-0321263373-43-8*WO 2011012661CK2CX-49451 nMTBB,CX-5011,CX-52791009820-21-621159648CLK1KH CB1919.7 nMCLK4,DYRK1ATG0031354037-26-521276940DYRK1HarmineDYRK1A:33 nM;DYRK1B:166 nMTG003442-51-319796173DYRK1BAZ19117 nM1594092-37-124134204ERK1/2SCH772984ERK1:4 nM;ERK2:1 nMGDC-0994,FR180204,VTX-11e(Erk2 only)942183-80-423614898ERK5XMD8-9280 nM(Kd)DCAMKL1,DCAMKL2 XMD17-1091234480-50-220832753GSK3/CHIR-99021GSK-3:10 nM;GSK-3:6.7 nMCHIR-98014,AR-A0144418,SB216763252917-06-922065134JNK1/2/3JNK-IN-8 JNK1:4.7 nM;JNK2:18.7 nM;JNK3:1nMJNK-9L,AS601245,SP6001251410880-22-622284361p38VX-745p38:10 nM;p38:220 nMLY2228820,PH-797804,BIRB796(allosteric)209410-46-824900264PI3KGDC-0941p110:3 nM;p110:33 nM;p110g:75 nM;p110:3 nM NVP-BKM120,XL-147957054-30-718754654PI3KBYL-719p110:5 nM;p110:1,200 nM;p110g:250 nM;p110:290 nM GDC-0032,INK11171217486-61-723726034PI3KAZD6482p110:870 nM;p110:10 nM;p110g:1090 nM;p110:80 nMTGX-2211173900-33-822906130PI3KCAL-101p110:820 nM;p110:565 nM;p110:2.5 nM;p110g:89 nMIC-87114,IPI-145,AMG-319870281-82-620959606PI3KgCZC24832p110g:27 nMPI3K,PIP4K2CAS-6052401159824-67-522544264Vps34SAR4051.5 nM(Kd)VPS34-IN1,PIK-III1523406-39-425326666CK1CAMKCMGCLipidAtypicalAGCSee online version for legend and references.708.e1 Molecular Cell 58,May 21,2015 2015 Elsevier Inc.DOI http:/dx.doi.org/10.1016/j.molcel.2015.05.001SnapShot:Kinase Inhibitors IJinhua Wang1,2 and Nathanael S.Gray1,21Department of Cancer Biology,Dana-Farber Cancer Institute,Boston,MA 02215,USA2Department of Biological Chemistry&Molecular Pharmacology,Harvard Medical School,Boston,MA 02115,USASelective small-molecule inhibitors of kinases can serve as powerful tools to elucidate biological function.Efforts to develop potential drug candidates have yielded a wealth of kinase inhibitors.However,selecting the optimal kinase inhibitor for a particular application can be challenging.While the optimal inhibitor will be application specific,we have attempted to summarize some of the best reported inhibitors for various kinases.Typical considerations for selecting kinase inhibitors include requirements for selectivity,potency,cellular and in vivo bioavailability,and commercial accessibility(Knapp et al.,2013;Cohen,2010).Because most kinase inhibitors target the highly conserved ATP-binding pocket,selectivity data have been emphasized(Davies et al.,2000;Bain et al.,2003,2007;Davis et al.,2011;Uitdehaag et al.,2012).Users are encouraged to always validate their results with more than one kinase inhibitor at concentrations as low as pos-sible and,ideally,to“rescue”the inhibitor-induced phenomena through expression of an inhibitor-resistant allele of the kinase(Cohen,2010;Clark et al.,2012).Kinase inhibitors are grouped by family(Manning et al.,2002).The first column of the table indicates the kinase family names.Inhibition constant(Ki)or dissociation constant(Kd)is listed for compounds without reported IC50.*This compound is only disclosed in patent application.Patent publication number is listed instead.ACKnOwleDgMenTSWe thank Dr.Philip Cohen(University of Dundee)and Dr.Taebo Sim(Korea Institute of Science and Technology)for their advice.RefeRenCeSBain,J.,McLauchlan,H.,Elliott,M.,and Cohen,P.(2003).Biochem.J.371,199204.Bain,J.,Plater,L.,Elliott,M.,Shpiro,N.,Hastie,C.J.,McLauchlan,H.,Klevernic,I.,Arthur,J.S.,Alessi,D.R.,and Cohen,P.(2007).Biochem.J.408,297315.Clark,K.,MacKenzie,K.F.,Petkevicius,K.,Kristariyanto,Y.,Zhang,J.,Choi,H.G.,Peggie,M.,Plater,L.,Pedrioli,P.G.,McIver,E.,et al.(2012).Proc.Natl.Acad.Sci.USA 109,1698616991.Cohen,P.(2010).Biochem.J.425,5354.Davies,S.P.,Reddy,H.,Caivano,M.,and Cohen,P.(2000).Biochem.J.351,95105.Davis,M.I.,Hunt,J.P.,Herrgard,S.,Ciceri,P.,Wodicka,L.M.,Pallares,G.,Hocker,M.,Treiber,D.K.,and Zarrinkar,P.P.(2011).Nat.Biotechnol.29,10461051.Knapp,S.,Arruda,P.,Blagg,J.,Burley,S.,Drewry,D.H.,Edwards,A.,Fabbro,D.,Gillespie,P.,Gray,N.S.,Kuster,B.,et al.(2013).Nat.Chem.Biol.9,36.Manning,G.,Whyte,D.B.,Martinez,R.,Hunter,T.,Sudarsanam,S.(2002).Science.298,1912-34.Uitdehaag,J.C.,Verkaar,F.,Alwan,H.,de Man,J.,Buijsman,R.C.,and Zaman,G.J.(2012).Br.J.Pharmacol.166,858876.