new anticancer drugs derived from plant hormones … · 2010-12-13 · laboratory of growth...
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Laboratory of Growth RegulatorsLaboratory of Growth Regulators
Miroslav StrnadMiroslav Strnad
Palacky University & Institute of Experimental Botany AS CRPalacky University & Institute of Experimental Botany AS CROlomouc, Czech RepublicOlomouc, Czech Republic
Olomouc
NEW ANTICANCER DRUGS DERIVED FROM PLANT
HORMONES (Olomoucines)
NEW ANTICANCER DRUGS DERIVED FROM PLANT
HORMONES (Olomoucines)
10/14/2008
LandmarksLandmarks
in Biology in Biology andand
GeneticsGenetics
Gregor Mendel
laws of genetics 1865
James
Watson
& Francis
Crick
double-helical structure of DNA 1953
Human
Genome
Project
10/14/2008
Institute of Experimental Botany
Academy
of
Sciences
of
the
Czech
Republic
10/14/2008
UNIVERSITASPALACKIANA
OLOMUCENSIS
10/14/2008
Co je Laboratoř
růstových regulátorů?
1.
Laboratoř
růstových regulátorů
je společným pracovištěm Ústavu experimentální
botaniky AVČR a Přírodovědecké
fakulty Univerzity
Palackého.
2. Byla založena v září
1996 jako výzkumné
pracoviště
interdisciplinárního charakteru.
3. Účelem pracoviště
je integrovat kapacity PřF UP a ÚEB AV ČR pro společné
řešení
vědecko-výzkumných projektů
v oblasti molekulárních a
fyziologických mechanismů
účinků
růstových regulátorů
u živých organismů.
10/14/2008
Co je Laboratoř
růstových regulátorů?
a)
pak přípravou nových, vysoce biologicky účinných růstových regulátorů
na bázi purinu,
b)
vývojem metod jejich analýzy,
c)
studiem jejich funkcí
a účinků
v růstových a vývojových procesech normální
a nádorové
buňky, včetně
vývoje
protinádorových
látek odvozených od rostlinných hormonů.
d)
studiem onkogenů
a nádorových supresorových
genů, mechanismů
regulace jejich exprese, včetně
vývoje
transgenních
organismů
kontrolovaně
exprimujících
různé
geny zapojené
v růstově-regulačních a obranných funkcích
organismů.
Pracoviště
se zabývá
vědecko-výzkumnou a pedagogickou činností
v oboru experimentální
biologie, zejména:
10/14/2008
Organizační
schéma LRR
Bioanalytickáchemie
Ondřej Novák
Bioorganickáchemie
Karel Doležal
Auxinya kys. abscisová
Jakub Rolčík
Inhibitory kinas
Vladimír Kryštof
Fytosteroidy
Jana Swaczynová
Enzymologie rostlin
Jitka Frébortová
Molekulárnífyziologie
Martin Fellner
Biomedicínckáchemie
Libor Havlíček
Cytokininy
Lukáš
Spíchal
Laboratoř
růstovýchregulátorů
Miroslav Strnad
10/14/2008
Publikační
aktivita LRR
Vědecké publikace LRR
0
5
10
15
20
25
30
35
40
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Rok
Poče
t pub
likac
í
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
Prům
ěrný
impa
kt fa
ktor
Počet článků v impakt. časopisechCelkový poč. publikací LRRPrůměrný impakt faktor
10/14/2008
N6-isopentenyladenine trans-zeatin dihydrozeatin
IsoprenoidIsoprenoid
andand
AromaticAromatic
CytokininsCytokinins
N
N NH
N
NH1
2
34
56 7
89
N
N NH
N
NH
OH
N
N NH
N
NH
OH
N
N NH
N
NH
N6-benzyladenine
N
N NH
N
NH
OH
meta-topolin
N
N NH
N
NH
OH
ortho-topolin
10/14/2008
7
93
Cytokinins (CK)Cytokinins (CK)
CK baseCK base
OH
OHN
N N
N
NH
R2
R1
CK CK ribotideribotide((ribosribosee--55´́MP)MP)
O
OHOH
OPO
OHO
CK OCK O--glucosideglucosideO O
OHOH
OHOH CK NCK N--glucosideglucoside
OOH
OHOH
OH
CK ribosideCK riboside
O
OH OH
OH
CKsCKs regulate cell division in shoots and roots, growth of regulate cell division in shoots and roots, growth of stems and roots and specific components of the cell cycle.stems and roots and specific components of the cell cycle.
CKsCKs overproduction is overproduction is implicated in plant tumour implicated in plant tumour developmentdevelopment..
CKsCKs promote chloroplast promote chloroplast development and cell development and cell extension in leaves and extension in leaves and cotyledons.cotyledons.
CKsCKs delay leaf delay leaf senescence. senescence.
10/14/2008
G1
G2S
M CDKCyclin
Cell Cell withwith ChromosomesChromosomes in in NucleusNucleus
DNA DNA SynthesisSynthesis
ChromosomeChromosomeDuplicationDuplication
CellCell with Duplicated Chromosomes
Chromosome Chromosome SeparationSeparation
MITOSISMITOSIS
Cell Cell DivisionDivision
Cell Cell CycleCycle
10/14/2008
Cell Cell CycleCycle andand CDKCDK
CDK4CDK4--66CyCycclinlin
DD
CDK1CDK1CyCycclinlin
AACDK2CDK2
CyCycclinlin
AA
CDK2CDK2Cyclin
E
CDK1CDK1CyCycclinlin
BB
G2
M
G1
S
G0
CDK /CDK /
cyclincyclinassociationassociation
peptide CDK inhibitor peptide CDK inhibitor associationassociation(INK4, CIP/KIP)(INK4, CIP/KIP) export from nucleusexport from nucleus
phosphorylationphosphorylation
(T161)(T161)
phosphorylationphosphorylation(T14, Y15)(T14, Y15)
cyclin cyclin synthesis / proteolysissynthesis / proteolysis
Regulation of CDK Regulation of CDK AActivityctivity
10/14/2008
CDK Regulation
CDK4CDK4--66Cyklin
D
CDK1CDK1Cyklin
ACDK2CDK2
Cyklin
A
CDK2CDK2Cyklin
E
CDK1CDK1Cyklin
B
G2
M
G1
S
G0
CDC25B
CDC25ACDC25C
CDC25B
CDC25BCDC25A
CDK7CDK7Cyklin
H
CDK7CDK7Cyklin
H
p21 CIP1
p57 KIP2p27 KIP1
p16 INK4Ap15 INK4B
p19 INK4Dp18 INK4C
Wee1Myt1
10/14/2008
transtranscriptioncription
E2FE2FDPDP
PP
CDK2CDK2Cyklin
E
p21 CIP1p27 KIP1 p16 INK4A
E2FE2F
PDPDP
CDK4CDK4--66Cyklin
D
pRB E2FE2FDPDP
p130 E2F
p107 E2F
pRB
transtranscriptioncription
G1
CDK CDK andand Cell Cell CycleCycle RegulationRegulation duringduring G1/S G1/S TransitionTransition
cc--mycmyc, cy, cycclinlin
E, cyE, cycclinlin
A, A, thymidinkinasthymidinkinasee, , ThymidylThymidylaatte e synthassynthasee, DNA , DNA polpol
αα,,
......
pRB
10/14/2008
CDK CDK andand G2/M G2/M TransitionTransition
APC
transitionG2/M
CDK1CDK1CyCycclinlin
BB
CDC25A
Cyclin
HCDK1CDK1
CyCycclinlin
AA
CyCycclinlin
FF
CDC25BCDC25C
Wee1Myt1 PKB/AKT
p90RSK
Erk1/2Importin
β
transport to nucleus
ssurvivinurvivinllaminamineses
nnuuccleolinleolinccondensinondensin
pperoxiredoxineroxiredoxin
PKA
Tome-1
Plk1CDK7CDK7
M
G2
10/14/2008Nature Reviews Cancer 1, 222-231 (2001)
Alterations of G1/S regulators
10/14/2008
NN
NN
NHR
12 3 4
56 78
9
freefree
basisbasis
Chemical
structure…NN66--substitutedsubstitutedderivativesderivatives
ofof
adenineadenine
OH
OH
isoprenoidisoprenoid aromaticaromatic
R
OO--glycosidesglycosides
9
7
3
3/7/93/7/9
NN--glucosidesglucosides99
ribosidesribosides
99
ribotidesribotides
Which of the biologically active cytokinins and Which of the biologically active cytokinins and cytokinin activate/inhibits cytokinin activate/inhibits cyclincyclin--depedentdepedent
kinaseskinases??
10/14/2008
human cyclin B / CDK1 complex produced via baculoviral expression system enzyme purification on Ni-NTA affinity column. assay in the presence of histone H1, ATP + [ - P] ATP and tested drug SDS gel electrophoresis, digital image analyser BAS-1800 graphic analysis (IC )
γ 33
50
SDS gel with reaction mixtures containing decreasingconcentrations of CDK inhibitor (BAS-1800 scan)
Dose-response curve of CDK inhibition by purine inhibitor
CDK CDK InhibitionInhibition
AssaysAssays
10/14/2008
ICIC5050
VValuesalues
forfor
VVariousarious
PPurinesurines
AAddeddded
toto PPurifiedurified
CDC2,CDC2,
CDK5 CDK5 andand
CDK4 CDK4 KKinasesinases
Compound IC 50(µM )
CDK1 CDK5 CDK4
6-substituted 6-aminopurine(adenine) 200 - -purines 6-dimethylaminopurine 120 120 -
6-allylaminopurine 50 100 >500isopentenyladenine 55 70 2006-benzylaminopurine 200 80 -6-furfurylaminopurine(kinetin) 180 - -trans-zeatin 70 150 >1000dihydrozeatin 80 - -cis-zeatin 150 100 -meta -topolin 70 - -ortho-topolin 200 - -6-(o-β-D-glucopyranosyl)-zeatin 850 - -
10/14/2008
Compound IC 50 (µM)CDK1 CDK5 CDK4
6,9-substituted adenosine 55 - -purines 6-benzylamino-9-(2-tetrahydropyranyl)purine(BPA) 200 160 -
dihydrozeatin
riboside >500 >500 -benzyladenosine >500 - -meta-topolin
riboside >500 - -ortho-topolin
riboside >500 - -zeatin riboside >500 >1000 -zeatin-9-glucoside >500 - -zeatin riboside-5´-monophosphate >500 - -
ICIC5050
VValuesalues
forfor
VVariousarious
PPurinesurines
AAddeddded
toto PPurifiedurified
CDC2,CDC2,
CDK5 CDK5 andand
CDK4 CDK4 KKinasesinases
10/14/2008
Compound IC 50(µM )CDK1 CDK5 CDK4
2,6,9- 2-amino-6- benzylamino -9- methylpurine 40 - -substituted 2-chloro-6- benzylamino -9- methylpurine 70 - -purines 2-(2- hydroxyethylamino )-6- amino -9- methylpurine 50 - -
2-(2- hydroxyethylamino )-6- benzylamino - 7 3 >10009-methylpurine (olomoucine )2-(2- hydroxyethylamino )-6- isopentenylamino -9- methylpurine 65 13 >10002-(2- hydroxyethylamino )-6- benzylamino -9- isopropylpurine 2 3 >10002-(R)-(1- hydroxymethyl /propylamino /)-6- benzylamino - 0.2 0.1 >5009- isopropylpurine (roscovitine )
ICIC5050
valuesvalues
forfor
variousvarious
purinespurines
addedadded
to to purifiedpurified CDC2, CDK5 CDC2, CDK5 andand
CDK4 CDK4 kinaseskinases
HYDROGEN BOND DONOR
HYDROGEN BOND ACCEPTOR
HYDROPHOBIC / LIPOPHILIC INTERACTIONS
CHARGE-TRANSFER INTERACTION
OOlomoucinelomoucine
andand
itsits
PPotentialotential
IInteractionsnteractions
withwith aa
BBindinginding
SSiteite
Enzyme IC50 (µ M)
olomoucine isopentenyladenine
p34 cdc2 /cyclinA 50 -p34 cdc2 /cyclinB 7 45p34 cdc2 /cyclinE 10 -p33 cdk2 /cyclinA 7 50p33 cdk2 /cyclinE 7 -p34 cdk4 /cyclinD >1000 200p35 cdk5 /35 3 80p40 cdk6 /cyclinD3 >250 >100GST- erk -1 30 90c-protein kinaseC α,β1,β2,γ >1000 40-100n-protein kinaseC δ,ε,η,ζ >1000 50-100cAMP -dependent
kinase >1000 50cGMP -dependent
kinase >1000 50Calmodulin -dependent
kinaseII >1000 >100Myosin
light -chain
kinase >1000 >1000AMP- activated protein kinase 230 >1000Insulin-receptor protein kinase 400 140DNA topoisomerase I, II 250 -DNA polymerase α,δ 500 -
ICIC5050
VValuesalues
forfor
OOlomoucinelomoucine
andand
IIsopentenyladeninesopentenyladenine AAddeddded
toto
VVariousarious
PPurifiedurified
KKinasesinases
10/14/2008
Double reciprocal plots of kinetic data from assays of pDouble reciprocal plots of kinetic data from assays of p34cdc234cdc2/cyclin B /cyclin B protein kinase activity at different concentrations of olomoucinprotein kinase activity at different concentrations of olomoucinee
10/14/2008
SchematicSchematic
DDrawingrawing
ofof
CDK2 CDK2 withwith
thethe
IInhibitor nhibitor RRoscovitine oscovitine SSuperimposeduperimposed
in in thethe
BBindinginding
PPocketocket
10/14/20086-benzylaminopurine Olomoucine Roscovitine
Compound IC / µM50
6-benzylaminopurine 200olomoucine 7roscovitine 0.2
DevelopmentDevelopment
ofof
PPurine CDKurine CDK22
IInhibitorsnhibitors
Olomoucine
II
olomoucine II 0.02
10/14/2008
TherapeuticalTherapeutical
EffectsEffects
ofof
CDK CDK InhibitorsInhibitors
Roscovitine
(Cyc202)
Int. J. Cancer 102, 463-468, 2002
ControlRoscovitine 200 mg / kgRoscovitine 500 mg / kg Days
Rel
ativ
etu
mor
siz
e
0
1
2
3
4
5
6
7
0 5 10 15
MOUSE XENOGRAFTS: LOVO AND MESSA-DX5 CARCINOMAS
Int. J. Cancer 102, 463-468, 2002
10/14/2008
Therapeutical
Effects
of
CDK Inhibitors
Sequential
combination:
1. Taxol
2. Purvalanol
A
Cancer Cell 2, 43-54, 2002ControlTaxol
(2,5 mg/ml)Taxol
(5 mg/ml)Taxol
(2,5 mg/ml) –
Purvalanol
ATaxol
(5 mg/ml) –
Purvalanol
ATaxol
(5 mg/ml) –
Purvalanol
A continuously
0 10 20 30 40 500
40
60
80
100
STOP
Days
Sur
viva
l(%
)
Intensive
apoptosesReduction
of
tumor
Low
toxicityUnlimited
survival
Carcinoma
MCF7
10/14/2008
Roscovitine in Roscovitine in CClinicallinical
TTrialsrials
RR--roscovitine (CYC202, roscovitine (CYC202, SeliciclibSeliciclib))
LicencedLicenced
to to CyclacelCyclacel
Ltd.Ltd.
SeliciclibSeliciclib
is currently in Phase II clinical is currently in Phase II clinical trials as a single therapy in multiple trials as a single therapy in multiple myeloma as well as two other Bmyeloma as well as two other B--cell cell hematological malignancies: Bhematological malignancies: B--cell cell Chronic Lymphocytic Leukemia and Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma. Mantle Cell Lymphoma. An additional Phase II clinical trial is in An additional Phase II clinical trial is in progress investigating the effects of progress investigating the effects of SSeliciclibeliciclib
in patients with Nonin patients with Non--Small Cell Small Cell Lung Cancer in combination with Lung Cancer in combination with gemcitabinegemcitabine
and and cisplatincisplatin. .
10/14/2008
Roscovitine Roscovitine ((SSeliciclibeliciclib))RR
––
ClinicalClinical
ResultsResults
Seliciclib:
Monotherapy
of hepatocelullar
liver carcinoma -
reduction 46%, data from clinical examinations of Cyclacel, Scotland
10/14/2008
Roscovitine Roscovitine ((SSeliciclibeliciclib))RR
––
ClinicalClinical
ResultsResults
Seliciclib: Monotherapy
of nazopharingal
carcinoma
associated with EBV infection (Epstein-Barr virus),
no drug available –
reduction >
50%, regression of neck metastasis lymph nodes
10/14/2008
List List ofof CDK inhibitorCDK inhibitors in s in clinicalclinical developmentdevelopment
Compound Structure Sponsor Comments Phase Route
Seliciclib(CYC202, R-roscovitine)
1 Cyclacel Selective CDK2-CDK7-CDK9 inhibitor II p.o.
Alvocidib(flavopiridol, HMR1275)
2 Sanofi-Aventis Promiscuous kinase inhibitor with potent CDK-inhibitory activity
II i.v.
UCN-01 3 Kyowa Hakko Kogyo
Promiscuous kinase inhibitor with CDK- inhibitory activity
II i.v.
E7070 (indisulam) 4 Eisai G1/S cell cycle agent with indirect effects on CDK function
I/II i.v.
SNS-032 (formerly BMS- 387032)
5 Sunesis Selective CDK2-CDK7-CDK9 inhibitor I i.v.
ON 01910.Na 6 Onconova Dual specificity non-ATP-competitive CDK1/PLK1 inhibitor
I i.v.
AZD-5438 Not disclosed AstraZeneca Not known I ?
ZK-CDK Not disclosed Schering AG Dual-specificity CDK2/VEGF-/PDGF-RTK inhibitor
I p.o.
PD 0332991 7 Pfizer Highly CDK4-selective with G1/S activity I p.o.
PHA-690509 Not disclosed Nerviano Medical Science
Not known I ?
JNJ-7706621 8 Johnson & Johnson Dual specificity CDK and ARK inhibitor Preclinical p.o.
Not disclosed Not disclosed Hoffmann-La Roche Not known Preclinical ?
GPC-286199 9 GPC Biotech Pan-CDK inhibitor with antimitotic activity Preclinical i.v.
10/14/2008
CDK inhibitorCDK inhibitors in s in clinicalclinical developmentdevelopment
N
N N
N
HN
NH
HO
1: Roscovitine (Cyclacel)
N
OHO
OOH
HO
Cl
2: Flavopiridol (Aventis/NCI)
NN
HN
O
NHO
OH
H
O
3: UCN-01 (Kyowa Hakko Kogyo)
HN HN
O N
SS
N
O
5: SNS-032 (Sunesis)
SO
O
O
O
O
O
HN
O.NaO
6: ON 01910Na (Onconova)
HN HN S
O
OS NH2O
O
N
N N
O
NH
N
NHN
O
7: PD 0332991 (Pfizer)
O
NH
N
O N
O
NNH
O
NH
NO
9: GPC-286199 (GPC Biotech)
4: E7070 (Eisai)
NH
N
NNNH2
OS
H2N O
O
F
F
8: JNJ-7706621 (Johnson & Johnson)
10/14/2008
CytokininCytokinin--LikeLike InhibitorsInhibitors ofof
CDK9 (CDK7) = Olomoucine IICDK9 (CDK7) = Olomoucine II
10/14/2008
MolecularMolecular
DDockingocking
Insight into the active site of CDK2 with a purine
bound.
10/14/2008
Olomoucine II: Olomoucine II: orthoortho--HydroxylatHydroxylateded
RRoscovitineoscovitine DerivedDerived
fromfrom
orthoortho--TopolinTopolin
10/14/2008
CDK2 / roscovitine co-crystal
BBiochemicaliochemical
AAspectsspects
ofof
RRoscovitineoscovitine
kinase
IC50
/ µMCDK1/B
2.7CDK2/E
0.84CDK4/D
14.2CDK7/H
0.49CDK9/T
0.72Erk2
1.17PKA
>100PKC
>100CHK1
>100c-Abl
>100
10/14/2008
Olomoucine II Olomoucine II IInteractionsnteractions
withwith
CDK2CDK2
Leu83
Lys89 Asp86
kinase
IC50
/ µMCDK1/B
2.7CDK2/E
0.1CDK4/D
20CDK7/H
0.45CDK9/T
0.06Erk2
32PKA
>100PKC
>100CHK1
>100c-Abl
>100
10/14/2008
N
N N
N
NH
OH
NH
Roscovitine
CYC202Seliciclib
N
N N
N
NH
OH
NH
OHOlomoucine II
Anticancer
effect
of
olomoucine II
olomoucine II
Mean
GI50
= 3.3 µM
roscovitine
Mean
GI50
= 19 µM
10/14/2008
feedbackloop
feedbackloop
PTEN Cyclin G
p53p53p53 MDM2MDM2
DNAPKDNAPKATMATM
DNA breaksDNA breaks
ATRATR Caseinkinase II
Caseinkinase II
UV radiationstress
UV radiationstress
p14ARFp14ARF
OncogenesOncogenes
Tsp1
Maspin GD-AIF
BAI1PERP NOXAScotin
Fas Bax PIDD
KILLER/DR5 P53AIP1
GADD45
Reprimo
14-3-3σ
p21
ApoptosisApoptosisCell cycle
blockCell Cell cyclecycle
blockblock
p53 signallingp53 signalling
StressStress
Stress signallingStress signalling
Increase
of
p53 levelTransactivationIncrease
of
p53 level
Transactivation
Expression
ofeffectorgenes
Expression
ofeffectorgenes
Inhibition
ofvascularizationInhibition
of
vascularization
10/14/2008
StabilizationStabilization
ofof
p53p53//InductionInduction
ofof
p21p21
G2
MG1
S
p21 CIP1apoptoses
CDK2CDK2Cyklin
E
CDK1CDK1Cyklin
B
Pp53MDM2p53
p14 ARF
PMDM2
DNA damage, hypoxia
and temperature
shock
...
Chk2
ATM
MDM2p14 ARF
10/14/2008
StabilizationStabilization
ofof
p53p53//IInductionnduction
p21 p21 expressionexpression
0 5 10 15 20 30 40 µM
p53
p21
PCNA
InductionInduction
ofof
p53p53--transcriptionaltranscriptional
activityactivityby olomoucine II in Arn8 by olomoucine II in Arn8 cellscells
withwithreporterreporter
systemsystem
AccumulationAccumulation
ofof
p53 p53 andand
p21p21WAFWAF
proteinsproteins
in olomoucine II in olomoucine II treatedtreatedMCF7 MCF7 cellscells
0
200
400
600
800
1000
1200
1 3 6 9 12 15 20 30 40 50 60 80
concentration
/ µM
posi
tive
cells
/ wel
l
olomoucine
IIroscovitine
10/14/2008
Anticancer activity of CDK inhibitors
Cell cycle arrestInduction of apoptosisActivation of p53
cyclin D
cyclin E
cyclin A
cyclin A
S
G2M
cyclin B
CDK4/6
CDK2
CDK2
CDK1
CDK1
G1
CDK7cyclin H
DNA
CDK8cyclin C
CDK9cyclin T
DNA
RNA polymerase II
RNA
RNA polymerase II
inhibitorinhibitor
10/14/2008
Cell Cycle. 2004 Oct;3(10):1259-62
Anticancer activity of CDK inhibitors
Pivotal
role for Mcl-1
in multiple
myeloma
cells.
Mcl-1
(a member of the Bcl-2 family)
antagonizes
apoptosis
upon
mitogenic
and
survival
stimuli. It
is rapidly degraded in response to cell death signals.
Cancer Res. 2005 Jun 15;65(12):5399-407.
Roscovitine inhibits
phosphorylation
of
RNA polymerase II
by CDK9.Inhibition of transcription exerts its greatest effect on gene products where both mRNA and
protein have short half-lives, resulting in rapid decline of the
protein levels. Mcl-1, crucial for the survival of a range of cell types
including multiple myeloma, is
rapidly
down-regulated, which precededs
the
induction of apoptosis.
10/14/2008
Roscovitine blocks transcription through combined inhibition of CDK2, CDK7 and CDK9. Being activated by roscovitine, tumor suppressor proteins pRB
and p53 potently repress
transcription factors necessary for RNA polymerase I (UBF), RNA polymerase II (e.g. E2F) and RNA polymerase III (TFIIIB).
10/14/2008
Structure of Structure of OurOur ResearchResearch
•• Cell CycleCell Cycle andand CDKsCDKs
•• CytokininCytokinin--Like Inhibitors of Cyclin Like Inhibitors of Cyclin --Dependent Dependent KinasesKinases 1/21/2
•• CytokininCytokinin--LikeLike InhibitorsInhibitors ofof CDK7 a CDK9 CDK7 a CDK9 –– p53 p53 activationactivation
•• SelectiveSelective InhibitorsInhibitors ofof CDK9CDK9
•• AnticAnticytokininsytokinins as as NewNew DatabaseDatabase for for DevelopmentDevelopment ofof CDK CDK InhibitorsInhibitors
•• AnticancerAnticancer DrugsDrugs CombiningCombining CDK CDK InhibitionInhibition withwith AntiinflammatoryAntiinflammatory propertiesproperties
•• AnticancerAnticancer DrugsDrugs ExhibitingExhibiting AntiviralAntiviral ActivitiesActivities
• oncology (new generation of drugs affecting cell cycle)oncology (new generation of drugs affecting cell cycle)
•• neurology (Alzheimerneurology (Alzheimer’’s disease, strokes disease, stroke))
•• virology (human cytomegalovirus, herpes virus ...)virology (human cytomegalovirus, herpes virus ...)
•• parasitologyparasitology
((PlasmodiumPlasmodium,,TrypanosomaTrypanosoma, , ToxoplasmaToxoplasma ...)...)
... and other diseases resulting from uncontrolled proliferation... and other diseases resulting from uncontrolled proliferation
atherosclerosisatherosclerosispostpost--angioplasticangioplastic
restenosisrestenosis
tumortumor
angiogenesisangiogenesisglomerulonephritisglomerulonephritispsoriasispsoriasis
CCDDKI KI TTherapeuticherapeutic
AApplicationspplications
Acknowledgement
Laboratory
of
Growth
RegulatorsPalacky University & Institute of
Experimental
Botany, OlomoucLibor HavlicekVladimir
KrystofKarel DolezalIgor PopaLukas
SpichalVera
SiglerovaJan Hanus
Marek ZatloukalOta BlahousekJosef HolikJarmila BalonovaMiloslava SubovaRene
LenobelOlga Hustakova
Laboratory
of
Cell Cycle
and
CytoskeletonInstitute of
Experimental
Botany, Olomouc
Pavla BinarovaVera
Cenklova
Universitaire
Instelling
AntwerpenHarry
van Onckelen
Zwi
BernemannKatrien
Vermeulen
Dirk
Van Bockstale
Medical
Faculty, Palacký University in OlomoucMarián HajdúchJaroslav Veselý
Cyclacel
LtdPeter M. Fisher
MOU BrnoMOU BrnoMOU BrnoBořivoj VojtěšekPetr Müller
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