ANTICANCER AGENTS PROTEIN KINASE INHIBITORS

ANTICANCER AGENTSANTICANCER AGENTSPROTEIN KINASE INHIBITORSPROTEIN KINASE INHIBITORS

Chapter 21Chapter 21

Protein KinasesProtein Kinases

•Enzymes that catalyse phosphorylation reactions on protein substrates•500-2000 estimated protein kinases in a cell•Protein kinases are present in the cytoplasm•Protein kinase receptors - dual role as receptor and enzyme•Overexpression can result in cancer•Tyrosine kinases, serine-threonine kinases and histidine kinases•ATP used as enzyme cofactor - phosphorylating agent

N

N N

N

N

O

OH OH

H H

H H

O P O

O

O

P O

O

O

P

O

O

O

H H

61

N

N N

N

N

O

OH OH

H H

H H

O P O

O

O

P O

O

O

H H

61

O P

O

O

O

Protein KinasesProtein KinasesTyrosine kinasesTyrosine kinases

HN

O

Protein Protein

H

OH

ATP ADP

HN

O

Protein Protein

H

OP

OHOH

O

Protein KinasesProtein KinasesSerine-threonine kinasesSerine-threonine kinases

Serine

HN

O

OH

Protein Protein

H

ATP ADP

HN

O

O

Protein Protein

H

PO OH

OH

Threonine

HN

O

H3C OH

Protein Protein

H

ATP ADP

HN

O

H3C O

Protein Protein

H

PO OH

OH

Protein KinasesProtein KinasesActive SiteActive Site

•Contains the binding site for the protein substrateContains the binding site for the protein substrate

•Contains the binding site for the ATP cofactorContains the binding site for the ATP cofactor

•Clinically useful inhibitors target the ATP binding siteClinically useful inhibitors target the ATP binding site

•ATP binding site is similar but not identical for all protein kinasesATP binding site is similar but not identical for all protein kinases

•Allows selectivity of inhibitor action Allows selectivity of inhibitor action

1. Protein Kinases1. Protein KinasesATP binding siteATP binding site

N

N

O

H

H

O

HN

H2NOC

H3C

H3C

O

SH3C

Gln-767

Met-769

Leu-768

Ribose pocket

Hydrophobic pocket

Cleft

N

N N

N

N

O

OH OH

H H

H H

O P O

O

O

P O

O

O

P

O

O

O

H H

HBD

HBAN

N N

N

N

O

OH OH

H H

H H

O P O

O

O

P O

O

O

P

O

O

O

H H

Protein KinasesProtein Kinases

•Purine base is buried deep into the binding site•Purine forms two hydrogen bonding interactions to the binding site•Ribose sugar binds to a ‘ribose binding pocket’ •Triphosphate chain lies along a cleft towards the enzyme surface•Triphosphate interacts with two metal ions and amino acids•Specificity surface is an area of unoccupied binding site•An empty hydrophobic pocket lies opposite the ribose binding pocket•The gatekeeper residue is an amino acid situated at the entrance to the hydrophobic pocket•The size of the gatekeeper residue is important in drug design•The nature of amino acids in the binding pockets is important to drug design

N

N

O

H

H

O

HN

H2NOC

H3C

H3C

O

SH3C

Gln-767

Met-769

Leu-768HBD

HBA

Ribose pocket

Hydrophobic pocket

CleftN

N N

N

N

O

OH OH

H H

H H

O P O

O

O

P O

O

O

P

O

O

O

H H

ATP binding siteATP binding site

Protein Kinase InhibitorsProtein Kinase InhibitorsNotesNotes

•Type I inhibitors act on the active conformation of the enzymeType I inhibitors act on the active conformation of the enzyme

•Type I inhibitors bind to the ATP binding site and block access to ATP Type I inhibitors bind to the ATP binding site and block access to ATP

•Type II inhibitors act on the inactive conformation of the enzymeType II inhibitors act on the inactive conformation of the enzyme

•Type II inhibitors bind to the enzyme and stabilise the inactive conformationType II inhibitors bind to the enzyme and stabilise the inactive conformation

•Type II inhibitors are likely to be more selectiveType II inhibitors are likely to be more selective

Type I inhibitorsType I inhibitorsGefitinib, erlotinib, SU11248 and seliciclibGefitinib, erlotinib, SU11248 and seliciclib

Type II inhibitorsType II inhibitorsImatinib, lapatinib, sorafenib and vatalanibImatinib, lapatinib, sorafenib and vatalanib

Gefitinib (Iressa)Gefitinib (Iressa)

NotesNotes•Developed by Astra ZenecaDeveloped by Astra Zeneca•Inhibits the kinase active site of the epidermal growth factor receptorInhibits the kinase active site of the epidermal growth factor receptor•The EGF-receptor is a tyrosine kinase receptorThe EGF-receptor is a tyrosine kinase receptor•Gefitinib is a 4-anilinoquinazoline structureGefitinib is a 4-anilinoquinazoline structure

N

N

HN

OMe

O N

O

F

Cl

4 6

7

3

1 Morpholine

Quinazoline

Aniline

Lead compoundLead compound


Notes Notes •The secondary amine, electron-donating substituents and small lipophilic group The secondary amine, electron-donating substituents and small lipophilic group are all important for activityare all important for activity•Useful Useful in vitroin vitro activity activity•Lower Lower in vivoin vivo activity due to rapid metabolism activity due to rapid metabolism•Metabolised by cytochrome P450 enzymesMetabolised by cytochrome P450 enzymes

N

N

HN

OMe

OMe

CH3

6

7

4

I; IC50 5 nM

Secondary Secondary amineamine

Small lipophilic groupSmall lipophilic group

Electron-donating Electron-donating substituentssubstituents

N

N

HN

OMe

OMe

CH3

6

7

4

I; IC50 5 nM

Metabolism of the lead compoundMetabolism of the lead compound


N

N

HN

OMe

OMe

II

OH

N

N

HN

OMe

OMe

CH3

III

OH

+Cytochrome Cytochrome P450 enzymesP450 enzymes

OxidationOxidation

N

N

HN

OMe

OMe

CH3

6

7

4

I; IC50 5 nM

Notes Notes •Methyl group and Methyl group and parapara-position of aromatic ring are susceptible positions -position of aromatic ring are susceptible positions •Blocking metabolism should improve the half life of the drugBlocking metabolism should improve the half life of the drug

Drug designDrug design


NotesNotes•Fluoro-substituent blocks Fluoro-substituent blocks parapara-hydroxylation of the aromatic ring-hydroxylation of the aromatic ring•Fluorine is similar in size to hydrogen and has no steric effectFluorine is similar in size to hydrogen and has no steric effect•Methyl group is replaced by a chloro substituent Methyl group is replaced by a chloro substituent •Chlorine and methyl group have similar sizes and lipophilicitiesChlorine and methyl group have similar sizes and lipophilicities•Chlorine acts as a bio-isotere for the methyl groupChlorine acts as a bio-isotere for the methyl group•Chlorine is resistant to oxidationChlorine is resistant to oxidation•Compound is less active Compound is less active in vitroin vitro, but more active , but more active in vivoin vivo

N

N

HN

OMe

OMe

Cl

F

IV: IC50 9 nM

N

N

HN

OMe

OMe

CH3

6

7

4

I; IC50 5 nM

Drug designDrug design


N

N

HN

OMe

OMe

Cl

F

IV: IC50 9 nM

NotesNotes•Morpholine ring increases water solubilityMorpholine ring increases water solubility•Morpholine nitrogen allows generation of water soluble amine saltsMorpholine nitrogen allows generation of water soluble amine salts•Spacer allows morpholine to protrude out of the active siteSpacer allows morpholine to protrude out of the active site•Remains solvated when the drug is boundRemains solvated when the drug is bound•Avoids a desolvation penaltyAvoids a desolvation penalty

MorpholineMorpholine

IonisableIonisableN

N

HN

OMe

OMe

CH3

6

7

4

I; IC50 5 nM

N

N

HN

OMe

O N

O

F

Cl

4 6

7

3

1

Gefitinib

SpacerSpacer

Gefitinib (Iressa)Gefitinib (Iressa)Binding interactionsBinding interactions•Identified by a molecular modelling experimentIdentified by a molecular modelling experiment•Gefitinib is docked with a model binding siteGefitinib is docked with a model binding site•Binds to the ATP binding siteBinds to the ATP binding site•Aniline ring occupies the normally vacant hydrophobic pocket opposite the ribose Aniline ring occupies the normally vacant hydrophobic pocket opposite the ribose binding pocketbinding pocket•Quinazoline binds to the same region as the purine ring of ATP Quinazoline binds to the same region as the purine ring of ATP

N

N

N

OMe

O

F

ClH

N

O

Hydrophobic pocket

Cleft

Met-769

OH2

Thr-830

N

N

N

OMe

O

F

ClH

N

O

HBA

HBA

Hydrophobic pocket

Cleft

Met-769

OH2

Thr-830

N

N

N

OMe

O

F

ClH

N

O

HBA

HBA

Hydrophobic pocket

Cleft

Met-769

OH2

Thr-830

N

N

N

OMe

O

F

ClH

N

O

3. Gefitinib (Iressa)3. Gefitinib (Iressa)

N

HN

O

OMe

OMeMethionine

MeSO3H

N

HN

O

OMe

OH

Phenol

Pyridine

Ac2O

N

HN

O

OMe

OAc

Protecting group

SOCl2

N

N

Cl

OMe

OAc

ArNH2

N

N

NHAr

OMe

OAc

Aniline substituent

NH4OH

MeOH

N

N

NHAr

OMe

OH

R2N(CH2)nBr

N

N

HN

OMe

O N

OAr

Synthesis of gefitinib and analoguesSynthesis of gefitinib and analogues

4. Lapatinib and Etlotinib4. Lapatinib and Etlotinib

NotesNotes•4-Anilinoquinazoline structures - compare gefitinib4-Anilinoquinazoline structures - compare gefitinib•EGF-receptor kinase inhibitorsEGF-receptor kinase inhibitors

Quinazoline ringQuinazoline ring

Aniline ringAniline ringO

F

Cl NH

N

N

O HN

SO2Me

LapatinibLapatinib Erlotinib (Tarceva)Erlotinib (Tarceva)ICIC5050 2 nM 2 nM

N

N

NH

O

O

OMe

OMe

4

Quinazoline ringQuinazoline ring

Aniline ringAniline ring

5. PKI 1665. PKI 166

NotesNotes•Pyrrolopyrimidine structurePyrrolopyrimidine structure•EGF-receptor kinase inhibitorEGF-receptor kinase inhibitor•Different binding mode from ATP or anilinoquinazolinesDifferent binding mode from ATP or anilinoquinazolines

OH

NHN

N

NH

Me

4

HBA HBD

PyrrolePyrrole

PyrimidinePyrimidine

5. PKI 1665. PKI 166Comparison of binding interactionsComparison of binding interactions•ATP and EGF-receptor kinase inhibitors all contain a pyrimidine ringATP and EGF-receptor kinase inhibitors all contain a pyrimidine ring•Different binding modes are possibleDifferent binding modes are possible

HBA HBD

HBD

HBA

OH

NHN

N

NH

Me

4

PKI 166PKI 166

N

N

N

OMe

O

F

ClH

N

O

N

N N

N

N

O

OH OH

H H

H H

O P O

O

O

P O

O

O

P

O

O

O

H H

GefitinibGefitinib

ATPATP

HBA

HBA

OH

NHN

N

NH

Me

4

PKI 166PKI 166

N

N

N

OMe

O

F

ClH

N

O

N

N N

N

N

O

OH OH

H H

H H

O P O

O

O

P O

O

O

P

O

O

O

H H

GefitinibGefitinib

ATPATP

6. Imatinib (Glivec or Gleevec)6. Imatinib (Glivec or Gleevec)

NotesNotes•First protein kinase inhibitor to reach the marketFirst protein kinase inhibitor to reach the market•Selective inhibitor for a hybrid tyrosine kinase (Bcr-Abl)Selective inhibitor for a hybrid tyrosine kinase (Bcr-Abl)•Bcr-Abl is active in certain tumour cellsBcr-Abl is active in certain tumour cells

N

N

N

HN

Me

NH

O

N

NMe

6. Imatinib (Glivec or Gleevec)6. Imatinib (Glivec or Gleevec)Lead compoundLead compound

N

N

HN

I

PyrimidinePyrimidine Anilino substituentAnilino substituent

•Phenylaminopyrimidine structurePhenylaminopyrimidine structure•Identified by random screening of compound librariesIdentified by random screening of compound libraries•Originally identified as a PKC inhibitorOriginally identified as a PKC inhibitor•PKC is a serine-threonine kinasePKC is a serine-threonine kinase

6. Imatinib (Glivec or Gleevec)6. Imatinib (Glivec or Gleevec)Drug designDrug design

N

N

HN

I

N

N

N

HN

II

3'

Inhibits tyrosine Inhibits tyrosine kinases as wellkinases as well

PyridinePyridine

Increased inhibition of PKCIncreased inhibition of PKC

IV(IC50 5 M)

N

N

N

HN

NH

OAmideAmide

IV(IC50 5 M)

N

N

N

HN

NH

O

ConformationalConformationalblockerblocker

6. Imatinib (Glivec or Gleevec)6. Imatinib (Glivec or Gleevec)Drug designDrug design

IV(IC50 5 M)

N

N

N

HN

NH

O

CGP 53716(IC50 0.1 M)

N

N

N

HN

Me

NH

O

ImatinibImatinib

N

N

N

HN

Me

NH

O

N

NMe

PiperazinePiperazine

SpacerSpacer

•Piperazine increases activity, Piperazine increases activity, selectivity and water solubilityselectivity and water solubility•Spacer inserted to avoid Spacer inserted to avoid aniline structureaniline structure

•Increased activity vs Increased activity vs tyrosine kinasestyrosine kinases•No activity against No activity against serine-threonine kinasesserine-threonine kinases

O NH

O

MeS

Met

Gatekeeperresidue

Hydrophobic pocketSelectivity region 1

O

Thr

O

OGlu

H

N

O

O2C Asp

H

Hydrophobic regionSelectivity region 2

6. Imatinib (Glivec or Gleevec)6. Imatinib (Glivec or Gleevec)Binding interactionsBinding interactions•Identified from a crystal structure of an inhibitor-Abl kinase complexIdentified from a crystal structure of an inhibitor-Abl kinase complex•Amide serves as an ‘anchoring group’ and orientates the moleculeAmide serves as an ‘anchoring group’ and orientates the molecule•Amide binds to Glu and Asp Amide binds to Glu and Asp •Glu and Asp are important to the catalytic mechanismGlu and Asp are important to the catalytic mechanism

N

NN

N

H

Me

N

H

O

N N Me

H

O NH

O

MeS

Met

Gatekeeperresidue


O

Thr

O

OGlu

H

N

O

O2C Asp

H


N

NN

N

H

Me

N

H

O

N N Me

H

O NH

O

MeS

Met

Gatekeeperresidue


O

Thr

O

OGlu

H

N

O

O2C Asp

H


N

NN

N

H

Me

N

H

O

N N Me

H

O NH

O

MeS

Met

Gatekeeperresidue


O

Thr

O

OGlu

H

N

O

O2C Asp

H



•Other interactions determine target selectivityOther interactions determine target selectivity•A hydrogen bond to the gatekeeper Thr is essential to activityA hydrogen bond to the gatekeeper Thr is essential to activity•NN-Alkylation eliminates activity-Alkylation eliminates activity

Binding interactionsBinding interactions

N

NN

N

H

Me

N

H

O

N N Me

H

O NH

O

MeS

Met

Gatekeeperresidue


O

Thr

O

OGlu

H

N

O

O2C Asp

H



•Molecular modelling studies suggest that the piperazinyl group interacts with a Molecular modelling studies suggest that the piperazinyl group interacts with a glutamate residueglutamate residue•Imatinib inhibits protein kinases containing this glutamate residue (Abl, c-Kit Imatinib inhibits protein kinases containing this glutamate residue (Abl, c-Kit and PDGF-R)and PDGF-R)

Piperazinyl Piperazinyl groupgroup

GluGlu

IonicIonicbondbond


Conformational Conformational blockerblocker

N

NN

N

H

Me

N

H

O

N N Me

H

O NH

O

MeS

Met

Gatekeeperresidue


O

Thr

O

OGlu

H

N

O

O2C Asp

H



•Conformational blocker aids selectivityConformational blocker aids selectivity•Binds to a hydrophobic pocket that is not accessible if a larger gatekeeper Binds to a hydrophobic pocket that is not accessible if a larger gatekeeper residue was presentresidue was present


N

NN

N

H

Me

N

H

O

N N Me

H

O NH

O

MeS

Met

Gatekeeperresidue


O

Thr

O

OGlu

H

N

O

O2C Asp

H


6. Imatinib (Glivec or Gleevec)6. Imatinib (Glivec or Gleevec)Drug resistanceDrug resistance•Mutation of the gatekeeper residue to isoleucine introduces resistance (T315I Mutation of the gatekeeper residue to isoleucine introduces resistance (T315I mutation)mutation)•Isoleucine unable to form an important hydrogen bond to the amineIsoleucine unable to form an important hydrogen bond to the amine

Mutation to IsoleucineMutation to Isoleucine

N

O

MeI

HC(OEt)2NMe2

N

O

NMe2

Phenylguanidinederivative

N

N

N

HN

Me

NO2

II

H2Pd/C

Reduction

N

N

N

HN

Me

NH2

III

N

N

N

HN

Me

NH

O

ArAmide

ArCOCl

Acylation

6. Imatinib (Glivec or Gleevec)6. Imatinib (Glivec or Gleevec)Synthesis of imatinib and analoguesSynthesis of imatinib and analogues

N

NN

N

H

Me

N

H

O

F3C

NN

Me

Nilotinib

Met-318

Thr-315

Glu-286

Asp-381

7. Second Generation Bcr-Abl inhibitors7. Second Generation Bcr-Abl inhibitors

Me

Cl

N

O

S

N

N

NN

Me

NN

OH

Dasatinib; BMS-354825

H

H

Met-318

Thr-315


N

HN

Cl Cl

OMe

CNMeO

ON

MeN

Bosutinib

NotesNotes•Inhibits two protein kinase targets (Abl and Src)Inhibits two protein kinase targets (Abl and Src)•Currently in clinical trialsCurrently in clinical trials•Less likely to fall prey to drug resistanceLess likely to fall prey to drug resistance

NotesNotes•Allosteric inhibitor of Bcr-AblAllosteric inhibitor of Bcr-Abl•Does not bind to ATP binding siteDoes not bind to ATP binding site•Stabilises inactive form of the enzymeStabilises inactive form of the enzyme•Binds to an autoregulatory cleftBinds to an autoregulatory cleft•Potential agent for treating leukaemiaPotential agent for treating leukaemia

NH

MeO

N

N

NH2

O

GNF-2

MeO

HN CO2H

Me

SO O OMe

MeO OMe

ON012380


NotesNotes•Binds to the protein substrate siteBinds to the protein substrate site•Currently under studyCurrently under study

8. Inhibitors of cyclin-dependent kinases8. Inhibitors of cyclin-dependent kinasesCyclin-dependent kinasesCyclin-dependent kinases

•CDKs are involved in control of the cell cycle and are overexpressed in many cancer cellsCDKs are involved in control of the cell cycle and are overexpressed in many cancer cells

•Serine-threonine kinasesSerine-threonine kinases

•Activated by cyclinsActivated by cyclins

•Inhibited by cyclin-dependent kinase inhibitorsInhibited by cyclin-dependent kinase inhibitors

•Synthetic inhibitors bind to the ATP binding siteSynthetic inhibitors bind to the ATP binding site

8. Inhibitors of cyclin-dependent kinases8. Inhibitors of cyclin-dependent kinases

N

OH

Me

HO

OH

O

O

Cl

Flavopiridol

HBAHBD

•Benzopyran binds to the adenine binding regionBenzopyran binds to the adenine binding region•Piperidine binds to the region occupied by the first phosphate of ATPPiperidine binds to the region occupied by the first phosphate of ATP•Phenyl lies over the ribose binding pocketPhenyl lies over the ribose binding pocket•Undergoing clinical trialsUndergoing clinical trials

BenzopyranBenzopyran

PiperidinePiperidine Phenyl Phenyl ringring

8. Inhibitors of cyclin-dependent kinases8. Inhibitors of cyclin-dependent kinases

N

OH

Me

HO

OH

O

O

Cl

Flavopiridol

HNR O

N NO

NHMe

MeO

Me

Staurosporine; R=H7-Hydroxystaurosporin; R=OH

7HBAHBD

BenzopyranBenzopyran

PiperidinePiperidine Phenyl Phenyl ringring

7-Hydroxystaurosporin is 7-Hydroxystaurosporin is undergoing clinical trialsundergoing clinical trials

Shows selectivity for CDK2Shows selectivity for CDK2Undergoing clinical trialsUndergoing clinical trials

R-Roscovitine (seliciclib)

N

N N

N

MeMe

HN

NH

HO

Me

9. Kinase Inhibitors of FGF-R and VEGF-R9. Kinase Inhibitors of FGF-R and VEGF-RFGF-R and VEGF-RFGF-R and VEGF-R

•FGF-R = fibroblast growth factor receptorFGF-R = fibroblast growth factor receptor

•VEGF-R = vascular endothelial growth factor receptorVEGF-R = vascular endothelial growth factor receptor

•Associated with angiogenesisAssociated with angiogenesis

•Inhibitors bind to the ATP binding siteInhibitors bind to the ATP binding site

•Currently undergoing clinical trialsCurrently undergoing clinical trials

•SU 5416 in clinical trials for SU 5416 in clinical trials for treatment of colorectal treatment of colorectal cancercancer•Oxindole binds to same Oxindole binds to same region as adenine of ATPregion as adenine of ATP

NH

O

NH

Me R

Me

SU 5416, R=HSU 6668, R=CH2CH2CO2H

9. Kinase Inhibitors of FGF-R and VEGF-R9. Kinase Inhibitors of FGF-R and VEGF-R

HBA

HBD

Phase III clinical trials in Phase III clinical trials in 20062006

N

N

HN

N

Cl

PTK 787 / ZK 222584

PyrrolePyrrole

OxindoleOxindole

AnilinoAnilinosubstituentsubstituent

PhthalazinePhthalazine

PyridinePyridine

10. Multi-tyrosine receptor kinase inhibitors10. Multi-tyrosine receptor kinase inhibitorsNotesNotes

•Designed to be selective against a range of tyrosine receptor kinases implicated in Designed to be selective against a range of tyrosine receptor kinases implicated in tumourstumours

•Drug resistance unlikely to occur for all kinase targetsDrug resistance unlikely to occur for all kinase targets

•Equivalent of combination therapy (poly-pharmacology)Equivalent of combination therapy (poly-pharmacology)

•Sometimes called ‘dirty drugs’Sometimes called ‘dirty drugs’

•Promising agents against tumours that are driven by several abnormalitiesPromising agents against tumours that are driven by several abnormalities

10. Multi-tyrosine receptor kinase inhibitors10. Multi-tyrosine receptor kinase inhibitors

NotesNotes•Sorafenib approved as a VEGF-R kinase inhibitorSorafenib approved as a VEGF-R kinase inhibitor•Sunitinib approved in 2006 - inhibits VEGF-R, PDGF-R and KIT receptor kinasesSunitinib approved in 2006 - inhibits VEGF-R, PDGF-R and KIT receptor kinases•Vatalanib undergoing clinical trialsVatalanib undergoing clinical trials

F

NH

O

NH

Me

Me

O

NH

NEt2

Sunitinib

N N

NH

N

Cl

Vatalanib

N

N

O

H3C O

NHN

OCl

CF3

Sorafenib IC50 12 nM

H

H

10. Multi-tyrosine receptor kinase inhibitors10. Multi-tyrosine receptor kinase inhibitorsDesign of sorafenibDesign of sorafenib•Lead compound found by high throughput screening Lead compound found by high throughput screening •200 000 compounds tested200 000 compounds tested•Tested against recombinant Raf-1 kinaseTested against recombinant Raf-1 kinase

UreaUreaHN

HN

OS

MeO2C

H

Lead compound; Lead compound; ICIC5050 17 17 MM

10. Multi-tyrosine receptor kinase inhibitors10. Multi-tyrosine receptor kinase inhibitorsDesign of sorafenib - variation of substituentsDesign of sorafenib - variation of substituents

HN

HN

OS

MeO2C

Me

II; ICII; IC5050 1.7 1.7 MM

HN

HN

OS

MeO2C

O

III; Poor activityIII; Poor activity

NotesNotes•Methyl substituent is optimum for activityMethyl substituent is optimum for activity•10-fold increase in activity10-fold increase in activity•Phenoxy group is bad for activityPhenoxy group is bad for activity

HN

HN

OS

MeO2C

H

Lead compound Lead compound ICIC5050 17 17 MM

10. Multi-tyrosine receptor kinase inhibitors10. Multi-tyrosine receptor kinase inhibitorsDesign of sorafenib - variation of ringsDesign of sorafenib - variation of rings

NotesNotes•Variation of rings also carried out systematicallyVariation of rings also carried out systematically•Isoxazole ring is not good for activityIsoxazole ring is not good for activity•Conventional medicinal chemistry strategies fail to achieve further improvementConventional medicinal chemistry strategies fail to achieve further improvement

VI; Poor activityVI; Poor activity

HN

HN

O

N

O

IsoxazoleIsoxazoleHN

HN

OS

MeO2C

H


10. Multi-tyrosine receptor kinase inhibitors10. Multi-tyrosine receptor kinase inhibitorsDesign of sorafenibDesign of sorafenib

NotesNotes•Parallel synthesis - 1000 analogues synthesised with all possible Parallel synthesis - 1000 analogues synthesised with all possible combinations of rings and substituentscombinations of rings and substituents•Structure IV has slightly increased activity - contradicts results from Structure IV has slightly increased activity - contradicts results from conventional studiesconventional studies•Isoxazole ring and phenoxy substituent are good for activity when combined Isoxazole ring and phenoxy substituent are good for activity when combined in the same structure - synergistic effectin the same structure - synergistic effect•Structure IV taken as new lead compoundStructure IV taken as new lead compound

HN

HN

OS

MeO2C

H

IV; ICIV; IC5050 1.1 1.1 MM

HN

HN

O

N

O

O


IsoxazoleIsoxazole

PhenoxyPhenoxygroupgroup

IV; ICIV; IC5050 1.1 1.1 MM

HN

HN

O

N

O

O


IV; ICIV; IC5050 1.1 1.1 MM

HN

HN

O

N

O

O

IsoxazoleIsoxazole


HN

HN

OS

MeO2C

H

PyridinePyridineHN

HN

O

N

O

O

N

V; ICV; IC5050 0.23 0.23 MM

•Ring variationRing variation•5-fold increase in activity5-fold increase in activity•Increase in aqueous Increase in aqueous solubility and cLogsolubility and cLogPP



HN

HN

OS

MeO2C

H


1000-fold increase in activity1000-fold increase in activity

N

N

O

CH3O

NHN

OCl

CF3

H

H

Sorafenib ICSorafenib IC5050 12 nM 12 nM

IV; ICIV; IC5050 1.1 1.1 MM

HN

HN

O

N

O

O

IsoxazoleIsoxazole


PyridinePyridineHN

HN

O

N

O

O

N

V; ICV; IC5050 0.23 0.23 MM

RingRingvariationvariation

SubstituentSubstituentvariationvariation

SubstituentSubstituentvariationvariation

N

N

O

CH3O

NHN

OCl

CF3

H

H

Sorafenib ICSorafenib IC5050 12 nM 12 nM

10. Multi-tyrosine receptor kinase inhibitors10. Multi-tyrosine receptor kinase inhibitorsSorafenib - binding interactionsSorafenib - binding interactions

NotesNotes•Urea functional group acts as a binding anchor (compare imatinib)Urea functional group acts as a binding anchor (compare imatinib)•Hydrogen bonds are formed to catalytic Asp and GluHydrogen bonds are formed to catalytic Asp and Glu•Binding orientates the moleculeBinding orientates the molecule•Positions each half into two selectivity regionsPositions each half into two selectivity regions

N

N

O

CH3O

NHN

OCl

CF3

H

H

HBA

HBD

HBA HBD

11. Inhibitors of heat shock protein 9011. Inhibitors of heat shock protein 90

NotesNotes

•HSP 90 is a kinase protein and acts as a molecular chaperoneHSP 90 is a kinase protein and acts as a molecular chaperone

•Important to survival of cells - inhibition likely to lead to cell deathImportant to survival of cells - inhibition likely to lead to cell death

•HSP 90 interacts selectively with many of the proteins implicated in tumoursHSP 90 interacts selectively with many of the proteins implicated in tumours

•Targeting HSP 90 may be effective against tumour cells resistant against other Targeting HSP 90 may be effective against tumour cells resistant against other drugsdrugs

•Resistant cells contain mutated proteins - rely more on HSP 90 during the Resistant cells contain mutated proteins - rely more on HSP 90 during the folding processfolding process

•Resistant cells likely to be more vulnerable to inhibitors of HSP 90Resistant cells likely to be more vulnerable to inhibitors of HSP 90

11. Inhibitors of heat shock protein 9011. Inhibitors of heat shock protein 90NotesNotesInhibitors bind to the ATP binding site Inhibitors bind to the ATP binding site Lead compound - geldanamycinLead compound - geldanamycin

OMeHN

O

OMeOOH

Me

O

MeOMeMe

MeO

H2N

O

•Natural productNatural product•Potent inhibitorPotent inhibitor•Urethane group is crucial to activityUrethane group is crucial to activity•Binds to region occupied by adenineBinds to region occupied by adenine•Poor solubilityPoor solubility•Reactive quinone moietyReactive quinone moiety

QuinoneQuinone

UrethaneUrethane

11. Inhibitors of heat shock protein 9011. Inhibitors of heat shock protein 90Geldanamycin analoguesGeldanamycin analogues

OMeHN

O

NH

OOH

Me

O

MeOMeMe

MeO

H2N

O

TanespimycinTanespimycin

OMeHN

O

NH

OOH

Me

O

MeOMeMe

MeO

H2N

O

NMe

AlvespimycinAlvespimycin

OMeHN

O

NH

HOOH

Me

OH

MeOMeMe

MeO

H2N

O

IPI 504IPI 504

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