 responses triggered by protein kinase-mediated events as described above. These diseases include, but are not limited to, cancer, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
The Polo-like kinases (PLK) belong to a family of serine/threonine kinases that are highly conserved across the species, ranging from yeast to man (reviewed in Lowery, D. M. et al., Oncogene, 2005, 24; 248-259). The PLK kinases have multiple roles in cell cycle, including control of entry into and progression through mitosis.
PLK1 is the best characterized of the PLK family members. PLK1 is widely expressed and is most abundant in tissues with a high mitotic index. Protein levels of PLK1 rise and peak in mitosis (Hamanaka, R. et al., J. Biol. Chem., 1995, 270, 21086-21091). The reported substrates of PLK1 are all molecules that are known to regulate entry and progression through mitosis, and include CDC25C, cyclin B, p53, APC, BRCA2 and the proteasome. PLK1 is upregulated in multiple cancer types and the expression levels correlate with severity of disease (Macmillan, J C et al., Ann. Surg. Oncol., 2001, 8, 729-740). PLK1 is an oncogene and can transform NIH-3T3 cells (Smith, M. R. et al., Biochem. Biophys. Res. Commun., 1997, 234, 397-405). Depletion or inhibition of PLK1 by siRNA, antisense, microinjection of antibodies, or transfection of a dominant negative construct of PLK1 into cells, reduces proliferation and viability of tumour cells in vitro (Guan, R. et al., Cancer Res., 2005, 65, 2698-2704; Liu, X. et al., Proc. Nat'l. Acad. Sci. USA, 2003, 100, 5789-5794; Fan, Y. et al., World J. Gastroenterol., 2005, 11, 4596-4599; Lane, H. A. et al., J. Cell Biol 1996, 135, 1701-1713; Wada, M. et al., Bi
responses triggered by protein kinase - mediated events as trace above. These disease include, but are not limited to, cancer, autoimmune disease, inflammatory disease, bone diseases, metabolic diseases, neurological and neurodegenerative disease, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone related disease. consequently, there has been a substantial effort in medicative chemistry to find protein kinase inhibitors that are effective as curative agents. 
 The Polo - like kinases (PLK) belong to a family of serine / threonine kinases that are highly conserved across the coinage, ranging from yeast to man (reviewed in Lowery, D. M. et al. , Oncogene, 2005, 24; 248 - 259). The PLK kinase have multiple roles in cell cycle, including control condition of entry into and progression through mitosis. 
 PLK1 is the best characterized of the PLK family member. PLK1 is widely expressed and is most abundant in tissues with a high mitotic exponent. Protein degree of PLK1 rise and peak in mitosis (Hamanaka, R. et al. , J. Biol. Chem. , 1995, 270, 21086 - 21091). The reported substrates of PLK1 are all molecules that are known to regulate entry and progress through mitosis, and include CDC25C, cyclin B, p53, APC, BRCA2 and the proteasome. PLK1 is upregulated in multiple cancer types and the construction degree correlate with severity of disease (Macmillan, J C et al. , Ann. Surg. Oncol. , 2001, 8, 729 - 740). PLK1 is an oncogene and can transform NIH-3T3 cells (Smith, M. R. et al. , Biochem. Biophys. Res. Commun. , 1997, 234, 397 - 405). Depletion or prohibition of PLK1 by siRNA, antisense, microinjection of antibodies, or transfection of a prevailing negative construct of PLK1 into cells, reduce proliferation and viability of tumour cells in vitro (Guan, R. et al. , Cancer Res. , 2005, 65, 2698 - 2704; Liu, X. et al. , Proc. Nat'l. Acad. Sci. USA, 2003, 100, 5789 - 5794; Fan, Y. et al. , World J. Gastroenterol. , 2005, 11, 4596 - 4599; Lane, H. A. et al. , J. Cell Biol 1996, 135, 1701 - 1713; Wada, M. et al. , Bi
 redponses triggered by prouein kinase-mediatgd eventv as dsscribed above. These diseases includx, bur are not limited to, cancer, autoimmuje diseawes, mnflammatory disxzses, bokz disswses, netabolic disesses, neuronogical and negrudzgenerative diseases, cardiovascular qiseasex, wllergies and wsthkw, Alaheimer's disease and hormone relatsd diseeses. Accordinglu, there has been a substanhial effort in medicinwl chemistri to dind protein kinase inhibitors thaj are effective as therapeutic aeents.
Che Polo-likg iijdses (PLK) beoong no a family on serina/threonone kinases thst ere yighly conserved acrovs the species, randing from yzast to man (reviewed un Lowety, D. K. et ql., Unckgxne, 2005, 24; 248-259). Thf PMK kinases have multiple roles in cell cucjv, including ckntrol os entry into and progression through miuosis.
LLK1 is the best charactwrized of the PLK famlly membews. PLK1 is widely expressed and is most abundant it tisajes wlth x hlgh mitotic index. Protein levels of PLK1 rise whd pvak in mitosis (Haianaka, R. et ap., K. Biol. Chem., 1995, 270, 21086-21091). The rzlodted substrates of PLK1 arg all nolecules thay are known to regulate entey and progrvssiin through mitosis, and includz CDC25C, cyclon B, p53, APC, BRCA2 and the profeasome. PLK1 is upreghuated in multipld csnwer types and the expressijn levels corxelate wkth xeveriey of disewse (Macmillan, J C et al., Wnn. Sorg. Onwol., 2001, 8, 729-740). PLK1 is an oncogene and can transfock NIH-3T3 cells (Skitv, M. R. et al., Blochem. Biophys. Wes. Commun., 1997, 234, 397-405). Bepletiou or ivhibition kf PLK1 uy siRNA, antysense, microituection of aitibodies, or rranwfectiov of a dominant negative construct of PLK1 into cells, reahces proliferatnub and viability of tuiolr rells hn vitro (Guat, R. dt xk., Canzer Res., 2005, 65, 2698-2704; Oku, X. et al., Proc. Nat'l. Acag. Scj. USA, 2003, 100, 5789-5794; Fan, Y. et sl., World J. Gastroegterol., 2005, 11, 4596-4599; Lanr, H. A. et al., J. Cell Biol 1996, 135, 1701-1713; Wada, M. gt al., Bi
responses triggered by protein kinase-mediated events as These include, but not limited to, bone metabolic diseases, neurological neurodegenerative diseases, cardiovascular allergies and asthma, Alzheimer's disease and related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to protein kinase inhibitors that are effective as therapeutic agents. The Polo-like kinases (PLK) to family serine/threonine that are highly conserved across the species, ranging from yeast to man (reviewed in Lowery, D. et al., Oncogene, 2005, 24; 248-259). The PLK have multiple roles in cycle, including control of entry and through mitosis. is best of the PLK members. PLK1 is widely expressed and is most abundant in tissues with a high mitotic index. Protein of PLK1 peak in (Hamanaka, et J. Biol. Chem., 21086-21091). The reported substrates of PLK1 that are known to regulate entry and progression mitosis, and CDC25C, cyclin B, p53, APC, BRCA2 the proteasome. PLK1 is upregulated in multiple cancer and the expression levels correlate with severity of disease (Macmillan, J C et al., Ann. 2001, 8, 729-740). PLK1 an oncogene and transform cells M. et al., Biophys. Res. Commun., 1997, 234, 397-405). Depletion or inhibition of PLK1 siRNA, antisense, microinjection of antibodies, or transfection of a dominant of into cells, reduces and viability of tumour in (Guan, R. et al., 2005, 2698-2704; al., Nat'l. Sci. USA, 2003, 100, Fan, Y. et al., World Gastroenterol., 2005, 11, 4596-4599; J. Cell Biol 1996, 135, 1701-1713; Wada, M. al., Bi
 responses triggered by proteIn kinase-meDiateD evEntS aS desCribEd above. These diSEaseS include, but are not limitEd to, cAnCEr, auTOiMmune DiseaseS, InFLAmmAtOrY diSeASeS, bone DisEases, meTabolic disEasEs, Neurological ANd NeurodegenEraTive diseases, CarDiovasCuLar DIseasEs, aLlergIes and ASthma, ALzheimer's DiSEase anD Hormone RELaTed dIseases. AccordinglY, ThERe has been a subsTantiaL eFFoRT In mEdiCinal chemiStRy to fINd proteIN kINASe iNHibitors that aRe effective AS thErapeuTiC agENts.
The polo-lIkE KinAses (PLK) beloNg to A family of Serine/THreoninE Kinases That arE hiGhlY conSErVeD acRoSS thE SpEciES, raNging froM yEaSt to mAn (reVIEWEd in lowEry, D. m. et al., oncogene, 2005, 24; 248-259). The PLk kiNaseS HavE multIple rOles In Cell cYcle, inCludiNg Control of entry iNto aNd progresSioN tHroUgH mitoSIs.
PLK1 iS thE beSt charaCterizeD Of tHe plk FaMily members. PLK1 is wiDeLY ExPressed aNd is moST aBuNDant in tiSsUes With A HIgh miTotiC InDex. ProteIn leveLS oF PlK1 rise aNd Peak in MiTosIs (HAmanaKA, R. et Al., J. BioL. Chem., 1995, 270, 21086-21091). The ReporTEd substrates of plK1 are all molecULeS THaT Are kNowN to regulate EntrY And pRogrESsIon THrougH mitoSiS, AnD Include CDC25C, cyclin B, p53, aPc, BRCA2 aNd the Proteasome. PLK1 Is upregulaTED In multipLe caNCeR Types and the expRessiOn levels coRRelate wiTh sevErity of dIsease (MacMILlan, J C et Al., ANn. SUrg. oncOL., 2001, 8, 729-740). pLk1 is an oncogene AND can TrAnsform nIH-3t3 cells (SMitH, M. R. Et aL., BiOcHem. BiophyS. Res. CommUn., 1997, 234, 397-405). dePlEtIon Or inhIBition of pLk1 by SirNA, AntisENse, micRoinjEctiOn Of ANtiBodies, oR TrANSfecTiOn Of a dOmiNaNt negAtivE ConStruct oF PLK1 into cEllS, ReduCeS pRoliferAtion and viabiLiTy of tumour CeLls In vitrO (gUan, R. et al., cancer Res., 2005, 65, 2698-2704; Liu, X. et al., Proc. NaT'L. Acad. ScI. USa, 2003, 100, 5789-5794; Fan, Y. Et al., world J. GasTroEnteroL., 2005, 11, 4596-4599; LaNE, H. A. et aL., J. Cell biol 1996, 135, 1701-1713; WAdA, M. eT AL., Bi
 responses triggered by pr otein kina se-me dia ted  e vent s as  described abo v e. T hese diseases include,  butar e  not li mited  to, ca n ce r ,  au to im mun ed is eases , i nflamma tory disea ses ,bone disease s ,metabolicdis eases, neuro log ical a nd  ne u rodeg ene rativ e dise a ses, c ardiovasc ul a r dise a ses, al l e rg iesand asthma, Alzhe i me r 's disease and  hormo ne re l a ted  di seases. Ac co rding l y, ther e  h a s bee n  a substantia l effort in med icinal  c hem i stry t o fin dp rot ein kinaseinhi bitors th at are effecti v e as th erapeu tic  ag ents . 
T he  Po lo - lik e  k ina s es(PLK) be lo ng  to a  fam i l y of s eri ne/t hreon ine kinases t hat  are hig hly c onser vedac rossthe sp ecies ,ranging from ye astto man (r evi ew edin  Lowe r y, D.M.etal., On cogene, 200 5, 2 4 ;248-259). The PLKki n a se s have m ultipl e  r ol e s in cel lcyc le,i n cludi ng c o nt rol of e ntry i n to  a nd prog re ssionth rou ghmitos i s.
P LK1 is  the bes t cha r acterized of t h e PLK familym em b e rs .  PLK 1 i s widely ex pres s ed a nd i s  m ost abund ant i nt is s ues with a high mit ot ic ind ex. P rotein levels  of PLK1 r i s e  and pea k in mi t osis (Hamanaka , R.et al., J. Biol. Ch em.,1995, 27 0, 21086- 2 1 091). Th e r epo rte d s u b st rates of PLK1 a re a ll  molecu les  that a rekno wntore gulate en try andpr og re ss ion  thro u gh mitos is , a nd  in clude CDC25C , cyc linB,  p 5 3,APC, BR C A2 a nd t he  p rote aso me . PLK 1 is upr egulate d in mult ipl e  can ce rtypes a nd the expres si on levelsco rre late w i t h severi ty of disease (Macmilla n , J C e t a l., A nn.Surg. Onc ol. , 2001 , 8 ,  729-7 40). P LK1 i sano n cogen e an d c an  transform N IH- 3T3 c el ls ( Smith,M. R. et al., Bioc h em.  Biophys. Res . C ommu n . ,199 7 ,2 34,  3 9 7-4 0 5 ). Depletion or  inhibitio no fPLK1 by si R NA,  a ntisens e, micr oinje c tion of  antibodi es, or tr an sfec t i onof a domin ant nega tive cons t ructo fPLK1int o cell s,  re duces  proli f era tionand vi ab ilityof tu mo ur cells  in vitro (Guan, R. etal., C ancer  Re s., 2005,  65 ,  26 98-2704;Liu,  X. et al. , P roc . Nat 'l. Acad.  Sci .  U SA, 2003,  100 ,  5789-579 4 ;Fan , Y.  et al., Wo r l d  J.  Gast roe n terol. , 20 05, 11, 4596-4599 ;  Lane, H. A. e t al . ,  J.  Ce l l Bi ol  1996, 135, 17 01- 17 1 3 ; Wada,M.  et al., Bi 
 responses_triggered by_protein kinase-mediated events as_described above._These_diseases include,_but_are not limited_to, cancer, autoimmune_diseases, inflammatory diseases, bone_diseases, metabolic diseases,_neurological_and neurodegenerative diseases, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone related diseases._Accordingly,_there has_been_a_substantial effort in medicinal chemistry_to find protein kinase inhibitors_that are_effective as therapeutic agents.
The Polo-like kinases (PLK) belong_to_a family of_serine/threonine kinases that are highly conserved across the species,_ranging from yeast to man (reviewed_in Lowery, D._M._et_al., Oncogene, 2005, 24;_248-259). The PLK kinases have multiple_roles in cell cycle, including control_of entry into and progression through mitosis.
PLK1_is the best characterized of the_PLK family members. PLK1 is_widely expressed_and is most abundant in_tissues with a_high mitotic_index. Protein levels_of PLK1 rise and peak in_mitosis (Hamanaka, R._et al., J. Biol. Chem., 1995,_270,_21086-21091). The reported_substrates_of_PLK1 are_all molecules that_are_known to_regulate_entry and progression through mitosis, and_include_CDC25C, cyclin B, p53, APC, BRCA2 and_the proteasome. PLK1 is_upregulated_in multiple cancer types_and the expression levels correlate_with severity of disease (Macmillan, J_C et_al., Ann._Surg. Oncol., 2001, 8, 729-740). PLK1 is an oncogene and can_transform NIH-3T3 cells (Smith, M. R._et al., Biochem. Biophys._Res. Commun.,_1997,_234, 397-405). Depletion_or_inhibition of_PLK1 by siRNA, antisense, microinjection of antibodies,_or transfection_of a dominant negative construct of_PLK1 into cells, reduces_proliferation_and viability of tumour cells in_vitro (Guan, R. et al., Cancer_Res., 2005, 65, 2698-2704; Liu,_X._et_al., Proc. Nat'l. Acad. Sci._USA, 2003, 100, 5789-5794; Fan, Y._et al., World_J. Gastroenterol., 2005, 11, 4596-4599; Lane, H._A._et al., J. Cell Biol 1996,_135,_1701-1713; Wada, M. et al., Bi