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