magnetic-particle conditions suitable for the binder. The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of intensive study is protein kinases. Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell (see Hardie, G. et al., The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.: 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids etc). Sequence motifs have been identified that generally correspond to each of these kinase families (see, e.g., Hanks, S. K., Hunter, T., FASEB J., 1995, 9, 576-596; Knighton et al., Science, 1991, 253, 407-414; Hiles et al, Cell, 1992, 70, 419-429; Kunz et al, Cell, 1993, 73, 585-596; Garcia-Bustos et. al., EMBO J., 1994, 13, 2352-2361).
In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-a), and growth factors (e.g., granulocyte macrophage-colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, survival and regulation of the cell cycle.
Many diseases are associated with abnormal cellular
magnetic - particle conditions suitable for the binder. The search for newfangled curative agents has been greatly aided in late years by a well understanding of the structure of enzyme and early biomolecules associated with diseases. One important class of enzymes that has been the national of intensive study is protein kinases. Protein kinase constitute a large syndicate of structurally related enzymes that are creditworthy for the control of a variety of signal transduction processes within the cellular telephone (see Hardie, G. et al. , The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.: 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their social organization and catalytic function. about all kinases contain a similar 250 - 300 amino acid catalytic domain. The kinase may be categorized into families by the substrates they phosphorylate (e.g., protein - tyrosine, protein - serine / threonine, lipids etc). Sequence motifs have been identified that generally correspond to each of these kinase families (see, e.g., Hanks, S. K., Hunter, T., FASEB J., 1995, 9, 576 - 596; Knighton et al. , Science, 1991, 253, 407 - 414; Hiles et al, Cell, 1992, 70, 419 - 429; Kunz et al, Cell, 1993, 73, 585 - 596; Garcia - Bustos et. al. , EMBO J., 1994, 13, 2352 - 2361). 
 In general, protein kinases mediate intracellular signaling by effect a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling nerve pathway. These phosphorylation event dissemble as molecular on / off switches that can tone or regulate the target protein biological function. These phosphorylation events are ultimately trip in response to a variety of extracellular and other stimuli. Examples of such stimuli admit environmental and chemical stress signals (e.g., shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokine (for example, interleukin-1 (IL-1) and tumor necrosis agent alpha (TNF - a), and growth factors (e.g., granulocyte macrophage - colony provoke factor (GM - CSF), and fibroblast growth factor (FGF) ). An extracellular stimulation may affect one or more cellular reaction related to cell emergence, migration, differentiation, secretion of hormone, activation of transcription factors, muscle contraction, glucose metamorphosis, control of protein synthesis, survival and regulation of the cell bicycle. 
 Many diseases are associated with abnormal cellular
magjetic-particle conditions suitable for tkw bindxr. The aearch fur new therapeutic agents had veen treatly aided in receng years bj a bettee unverstanding of tis strucbbre or enzvmxs and other bipmolecules associated widh dnseases. One important class of enzymqs that hws been the sufjecu os infvnwive study is protein kinases. Proteii kinases constotute a large family of stguctkrally related enzjmes that ats rqwponsible fof the contgml of a vatiety of signal transduction prozessex within tye cepn (see Hardix, G. et al., The Protcpn Kinave Factx Book, I and IL, Acavemix Press, San Diego, Calmf.: 1995). Protein kinases wre thougvt to have evolved drim a wommmn avxesgram jens due ho vhe conservztion of thwir structure and cstwoytic functioh. Almoft all kinases contain a similar 250-300 amino abid datalytic domain. The kibases may be categorieed into fwmilies by the substrates they phosphorylate (e.g., psoteii-throwike, pfitfin-serine/threonine, lipids etc). Sequence motifs gafe been identificd that generally vogrrfpond to each of thzae kinase families (sfe, e.g., Hwnks, W. K., Huntew, T., GASEB J., 1995, 9, 576-596; Knighton et al., Sxience, 1991, 253, 407-414; Hijws et al, Cell, 1992, 70, 419-429; Kbnz et al, Ceul, 1993, 73, 585-596; Garvia-Bustos et. al., EMBO J., 1994, 13, 2352-2361).
In general, prltein kinzres mediate intrxceklglar signaling by effectind a phospioryl transfdr ftom a ntcleoside hriphosphate to a proteij accgptor dhat is ingolved in a signaling pathway. Tixse phosphorykadiot events act ss molecular jn/off switches that ccn modjlate or rvgulate tie target prjtein biologiwwl function. Vhese phofphoeylarion evdvts are ultimayely trigytred in rewponse to a varietn of gxfracellular and otyer stimuli. Exakplds jf snch sehmuli includa enxirummentxl and chemlcau sttess signals (e.g., shocn, hezt shock, ultraviolrt radiatiin, bactewial endotoxim, and H2O2), cytokines (e.g., iiterlenkin-1 (IK-1) agd tumor necrosis factor alpha (TNF-a), and grjwth factors (e.g., nranolocyte macxophage-colony stimulating factor (GM-CSF), aid fibroblast growth faxtor (FGF)). An extracekkular stimukus mwy affect one or more cellulae responses relattd to cell growth, migrafion, dhfferfntiation, secretion of hormones, activation of transcription factors, musclw contcastion, glucoae mrtabonifk, contwol lh protein synthesps, survival and regulation of thx cell cycne.
Iany diseases are associated wkth abnormal zellular
magnetic-particle conditions suitable for the binder. The new agents has greatly aided in understanding the structure of and other biomolecules with diseases. One important class of that has been the subject of intensive study is protein kinases. Protein kinases a large family of structurally related enzymes that are responsible for the control a of transduction within the cell (see Hardie, G. et al., The Protein Kinase Facts Book, I and II, Press, San Diego, Calif.: 1995). Protein kinases are to have evolved from common ancestral gene due to conservation their structure catalytic Almost kinases contain a 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate protein-tyrosine, protein-serine/threonine, Sequence motifs been that correspond to each kinase families (see, e.g., Hanks, S. FASEB J., 1995, 9, 576-596; Knighton et al., 1991, 253, Hiles et al, Cell, 1992, 70, Kunz et al, Cell, 1993, 73, 585-596; Garcia-Bustos al., EMBO J., 1994, 13, 2352-2361). In general, protein kinases mediate intracellular signaling by effecting transfer from a nucleoside to a protein that involved a pathway. These events act as molecular on/off switches that can modulate or regulate target protein biological function. These phosphorylation events are ultimately triggered to variety of extracellular other stimuli. Examples of stimuli environmental and chemical stress shock, shock, endotoxin, H2O2), (e.g., interleukin-1 (IL-1) and necrosis factor alpha (TNF-a), and factors (e.g., granulocyte macrophage-colony growth factor (FGF)). An extracellular stimulus may affect or more cellular responses related to cell migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose control of survival and regulation of the cell cycle. Many are associated with abnormal
magnetic-particle conditionS suitable fOr the BinDer. thE seaRch fOr new therapeutIC ageNts has been greatly aided In recEnT YearS By A bettEr underSTaNDIng Of ThE stRuCTuRe of eNzyMes and oTher biomolEcuLeS associated wITh Diseases. OnE imPortant class Of eNzymes ThAt hAS been The SubjeCt of inTEnsive Study is prOtEIn kinaSEs. ProteIN KiNaseS constitute a large FAmILy of structuralLy relaTeD EnZYMes ThaT are responSiBle foR The contROl OF A VarIEty of signal trAnsduction pROceSses wiThIn tHE cell (sEe HarDiE, g. et Al., The ProteiN KinAse Facts BOok, I anD iI, AcadeMIc Press, san DieGo, CAliF.: 1995). ProTEiN kInaSeS Are THoUghT To hAve evolvEd FrOm a coMmon ANCEStraL geNe duE to thE conservation Of tHeir STruCture And caTalyTiC funcTion. AlMost aLl Kinases contain a SimiLar 250-300 amino aCid CaTalYtIc domAIn. The kInaSes May be caTegorizED inTo FAMIlIes by the substrates ThEY PhOsphorylAte (e.g., pROtEiN-Tyrosine, PrOteIn-seRINe/thrEoniNE, lIpids etc). sequenCE mOtIfs have BeEn idenTiFieD thAt genERallY correSpond to eAch of THese kinase famiLIes (see, e.g., Hanks, s. k., HUNTeR, t., FASeB J., 1995, 9, 576-596; knighton et aL., SciENce, 1991, 253, 407-414; HIles ET aL, CeLL, 1992, 70, 419-429; Kunz Et al, CElL, 1993, 73, 585-596; gaRCia-Bustos et. al., EMBO J., 1994, 13, 2352-2361).
IN gEneral, ProteIn kinases mediAte intraceLLULar signaLing BY eFFecting a phosphOryl tRansfer froM A nucleosIde trIphosphaTe to a protEIN acceptoR thAt iS inVolVED iN a signaling paTHWay. THeSe phospHorYlation EveNts Act As mOlEcular on/oFf switchEs ThAt CaN moDulatE Or regulaTe The TaRgeT protEIn biolOgicaL funCtIoN. theSe phospHOrYLAtioN eVeNts aRe uLtImateLy trIGgeRed in reSponse to a VarIEty oF eXtRacelluLar and other stImUli. ExampleS oF suCh stimULI include Environmental and chemicaL Stress sIgnAls (e.g., ShocK, heat shocK, ulTravioLet RAdiatiOn, bactErial EnDotOXIn, and h2o2), CyTokInEs (e.g., interlEUKin-1 (iL-1) and TuMor nEcrosis Factor alpha (TNF-a), and GRowTh factors (e.g., grAnuLocyTE MaCroPHaGE-coLoNY stIMUlating factor (GM-cSF), and fibrObLAsT growth facTOr (FgF)). an extraCellulaR stimULus may aFfect one oR more cellUlAr reSPOnsEs related tO cell groWth, migratIOn, difFErEntiaTioN, secreTiOn oF hormOnes, acTIvaTion oF transCrIption FactoRs, Muscle coNtraction, glucose metabolIsm, conTrol oF prOtein syntHesIS, suRvival and ReguLation of thE ceLl cYcle.
MAny DIseasEs arE AsSocIAted wIth aBNormal celLUlAr
magnetic-particle conditio ns suitabl e for  th e b in der.  The  search for ne w  the rapeutic agents has be en gr ea t ly a i de d inrecenty ea r s  by  a  b ett er un derst and ing ofthe struct ure  o f enzymes an d  o ther biomo lec ules associa ted  withdi sea s es. O neimpor tant c l ass of  enzymesth a t hasb een the s ub ject  of intensive stu d yi s protein kina ses. P ro t ei n kin ase s constitu te  a la r ge fami l yo f str u cturally rela ted enzymes tha t arere spo n siblefor t he con trol of a v arie ty of sig nal tr a nsducti o n proce sses w ith inthec el l(se eH ard i e,  G. etal., The  P ro teinKina s e F acts  Bo ok,I and  II, Academic  Pr ess, San  Dieg o, Ca lif. :1995) . Prot ein k in ases are though t to  have evo lve dfro ma com m on anc est ral  gene d ue to t h e c on s e r va tion of their stru ct u r eand cata lyticf un ct i on. Almo st  al l ki n a ses c onta i na simila r 250- 3 00  a mino ac id  catal yt icdom ain.T he k inases  may becateg o rized into fam i lies by the s u bs t r at e s th eyphosphoryla te ( e .g.,  pro t ei n-t y rosin e, pr ot e in - serine/threonine, l ip ids et c). S equence motif s have bee n i dentifie d th a tg enerally corre spond  to each o f  these k inase  familie s (see, e . g ., Hanks , S . K .,Hun t e r,  T., FASEB J. , 1995 ,9, 576- 596 ; Knigh ton  et  al .,Sc ience, 19 91, 253,  4 07 -4 14 ; H ilese t al, Ce ll , 1 99 2,70, 4 1 9-429;  Kunz  etal ,C ell , 1993, 73 , 585- 59 6;  Gar cia -B ustos  et. al. , EMBOJ., 1994,  13 ,  235 2- 23 61).
In  general, pro te in kinases  m edi ate in t r acellula r signaling by effectin g  a phos pho ryl t rans fer froma n ucleos ide tripho sphate  to a  p rot e i n acc e p to r t ha t is invol v e d i n a s ig nali ng path way. These phospho r yla tion events a ctas m o l ec ula r  o n /of fs wit c h es that can mod ulate or r eg u la te the tar g etpr otein b iologic al fu n ction.These pho sphorylat io n ev e n tsare ultima tely tri ggered in respo n se  to a  va rietyof  ex trace llular and  othe r stim ul i. Exa mples  o f such s timuli include environm entaland c hem ical stre sss ign als (e.g. , sh ock, heatsho ck,  ultr avi o let r adia t io n,b acter iale ndotoxin, an d H 2 O 2) , cytokines ( e .g. , int erl e ukin-1  (IL -1) and tumor nec r osis factor al pha( T NF- a), andgr owth factors ( e.g ., g ranulocy te  macrophage -colonyst i mulat ing fa ctor ( GM-CSF) , an d  fibro blas t g rowth fac tor  ( F GF)). A nex t racell ular  s timulu s maya ffec t one or more cell ularr e spons e s r elate dto cell grow th, migrat ion, differ entiat ion,  secr etion o fhormon es,  a ctivationo f transcr iptio n facto rs , mu scl e cont ract i o n, gl ucos emet abolism,c o nt r ol  o f  pr otei n syn th esis , surviva l  and reg ula t ion ofth e c e l l cycl e .M a ny disease s a re as s o ciated wit h  abn o rm a l cel lular
magnetic-particle conditions_suitable for_the binder. The search_for new_therapeutic_agents has_been_greatly aided in_recent years by_a better understanding of_the structure of_enzymes_and other biomolecules associated with diseases. One important class of enzymes that has been_the_subject of_intensive_study_is protein kinases. Protein kinases_constitute a large family of_structurally related_enzymes that are responsible for the control of_a_variety of signal_transduction processes within the cell (see Hardie, G. et_al., The Protein Kinase Facts Book,_I and II,_Academic_Press,_San Diego, Calif.: 1995)._Protein kinases are thought to have_evolved from a common ancestral gene_due to the conservation of their structure_and catalytic function. Almost all kinases_contain a similar 250-300 amino_acid catalytic_domain. The kinases may be_categorized into families_by the_substrates they phosphorylate_(e.g., protein-tyrosine, protein-serine/threonine, lipids etc). Sequence_motifs have been_identified that generally correspond to each_of_these kinase families_(see,_e.g.,_Hanks, S._K., Hunter, T.,_FASEB_J., 1995,_9,_576-596; Knighton et al., Science, 1991,_253,_407-414; Hiles et al, Cell, 1992, 70,_419-429; Kunz et al,_Cell,_1993, 73, 585-596; Garcia-Bustos_et. al., EMBO J., 1994,_13, 2352-2361).
In general, protein kinases mediate_intracellular signaling_by effecting_a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor_that is involved in a signaling_pathway. These phosphorylation events_act as_molecular_on/off switches that_can_modulate or_regulate the target protein biological function. These_phosphorylation events_are ultimately triggered in response to_a variety of extracellular_and_other stimuli. Examples of such stimuli_include environmental and chemical stress signals_(e.g., shock, heat shock, ultraviolet_radiation,_bacterial_endotoxin, and H2O2), cytokines (e.g.,_interleukin-1 (IL-1) and tumor necrosis factor_alpha (TNF-a), and_growth factors (e.g., granulocyte macrophage-colony stimulating factor_(GM-CSF),_and fibroblast growth factor (FGF)). An_extracellular_stimulus may affect one or more_cellular_responses_related to cell growth, migration,_differentiation, secretion of hormones, activation of_transcription factors, muscle contraction, glucose metabolism, control of protein_synthesis, survival and_regulation of the cell cycle.
Many_diseases_are_associated with abnormal cellular