Download A Medicinal Chemistry Perspec8ve on Picking the Right

AMedicinalChemistryPerspec4veonPickingtheRight
ScreeningStrategy
10thANNUALDRUGDISCOVERYFOR
NEURODEGENERATIONCONFERENCE
March7,2016
DaveSwinney
InsEtuteforRareandNeglectedDiseasesDrug
Discovery
www.irnd3.org
Takehomemessages
MolecularmechanismsofacEon(MMOAs)thatconnect
genotypetophenotypeareaprioridifficulttopredict
Empirical(phenotypic)approachestoidenEfyMMOAsand
correspondingleadmoleculesaremoresuccessfulforfirst-inclassmedicines
Outline
Part1.Howmedicineswork.
Part2.Howmedicineswerediscovered.
R&Disaitera4veprocess
MedicalNeed
Basicresearch
TranslaEonbiomarker
DrugApproval
Phase3Efficacy
Development
Drugdiscoveryis
aniteraEveprocess
starEngwithanunmet
medicalneedand
anideatoaddress
thatneed.
Proofofconcept
Clinicalsafety
StarEngpt(assay/target)
Discoverystrategy
Leadiden'fica'on
Discovery
Pharmacologicalmechanism
Leadop'miza'on
DrugCandidates
Part1.Howdomedicineswork?
Genotype
Target
Medicine
Pa4ent
We look for knowledge to provide a blueprint for discovery and
initial use of the medicines.
Determineac4vitybyIC50s(EC50s)forac4vecompounds
KI
E+I EI
FracEonaloccupancy=[I]/([I]+KI)
Assumeonesitebinding
ΔG=-RTln(KI)
ForKI=1nM
1.0
0.1
1
3
10
100
9%
50%
75%
91%
99%
fraction occupancy
[I, nM] % occupancy
IC50
0.8
0.6
0.4
0.2
0.0
0.001
0.01
0.1
1
10
[Inhibitor, nM]
100
1000
TheMedicinalChemist’sJugglingAct
SelecEvity/
Safety
Bioavailability
Biological
AcEvity
PharmaceuEcs/
Scale-up
Intellectual
Property
PharmacophoreIden4fica4on
•  PaulEhrlich:Apharmacophoreisamolecularframeworkthat
carriestheessenEalfeaturesresponsibleforadrugsbiological
acEvity*
•  ThepharmacophorewilldisplaythekeybindinginteracEons
betweenligandandtarget
Dtsch.Chem.Ges.1909,42,17
–  8.
ExampleofPharmacophoreIden4fica4on
SystemaEcstructuralmodficaEonstoidenEfypharmacophoreandestablishSAR
O
O
Move or remove
methoxy
Trim naphthyl
H
O
SO2NH2
SO2NH2
O
Less Potent
Maintains activity
O
SO2NH2
Hit Molecule
O
Remove naphthyl
O
Move or remove
sulfonamide
O
O
SO2NH2
Less potent
H
Less Potent
9.
Doseresponsecurves(IC50)canshiRbetweenassayformats
Fractional activity
FracEonaloccupancy =Drug/(Drug+KI)
1.2
1.0
Invitroac4vity
0.8
0.6
func4onalac4vity
0.4
0.2
0.0
0.01
0.1
1
10
100
1000
[inhibitor]
Invitro-purifiedprotein-target
FuncEonal-cells,Essues,animals-phenotypic
Howdomedicineswork?
Drugac4onbeginswithbinding
‘Corporanonaguntenisifixata’
Asubstancewillnotworkunlessitis
bound
-PaulEhrlich,1913
Ploeger BA, van der Graaf PH, Danhof M. Drug Metab Pharmacokinet. 2009;24:3-15.
MolecularMechanismofAc4on(MMOA)
•  MMOA:mechanismthroughwhichspecificmolecular
interacEonsbetweenthedruganditstargetresultina
effecEveandsafepharmacologicalresponse.
–  Includesbindingkine4candconforma4onalchangesthatspecifically
provideatherapeuEcallyusefulresponse.
MMOA-pharmacologicalhotspot
Aspirinandibuprofen
twomedicines,onetarget,differentmolecularmechanisms,
differentuses
•  AspirinhasanE-plateletacEvitywhereasNSAIDsdonot.
–  EffecEveforprevenEonofatherothromboEcdisease
•  BothbindtotheacEvesiteofcyclooxygenase1and2
–  AspirinirreversibleinacEvaEonviaacetylaEonofSer530
–  IbuprofenandotherNSAIDSarereversible
•  IrreversibleacEonofaspirininplateletsleadstolonglasEnganEthromboEceffects
–  Plateletsdonothavethecapacitytoresynthesizenewprotein
Substrate –arachidonic acid
aspirin
ibuprofen
estrogenreceptormodulators
onetarget,differentmolecularmechanisms,differentuses
LigandinducedconformaEonalchangesrecruitcoacEvatorsandcorepressorsina
contextspecificmanner.
DifferenEatedtherapeuEcusedepends
onuniqueligandinducedconformaEons.
Estradiolagonist
-postmenopausalhormone
deficiency
TamoxifenSERM(selecEve
estrogenreceptormodulator)
-breastcancer
RaloxifenSERM
-osteoporosis
ERligand
bindingdomain
Brzozowski,AMetalNature389,753(1997).
14
•  Communica4onofinforma4onasananalogyofMMOA
–  ProximityisrarelysufficientforeffecEvesharingofspecificinformaEon
–  MMOAisalanguagetocommunicatespecificinforma4on.
‘Pharmacologicalhotspots’
Part2.Howweremedicinesdiscovered.
Defini4on
phenotypicscreening-anyscreeninginwhichthemolecularmechanismof
acEon(MMOA)thatprovidesatolerabletherapeuEcindexisnotassumed.
–  Inthiscontextthephenotypicscreeningisasynonymforempirical
screening.
Empiricalscreening
MedicinalchemistryevolvedfromtheisolaEonandidenEficaEonoftheacEveingrediantsofthesenatural
products,followedbythestudyoftheirmechanismofacEononbiologicalprocesses
R1
O
OH
O
H
N
HO
H
N Me
R2 O
Opium:
Morphine(R1,R2=H)
Codeine(R1=Me,R2=H)
MeO
Me
N
Me
N
Quinine
Ephedrine
17.
Concludethevalueofphenotypicassaysistodiscover
MajorityofFirstinclassmedicinesdiscoveredwith
newMMOAswhicharedifficulttoaprioripredict
empiricalassays
NMEsapprovedFDA1999-2008
259total
183smallmolecules
20imagingagents
56therapeuEcbiologics
75firstinclass
164followers
Themajorityofsmallmolecule
-firstinclassmedicineswere
discoveredwithphenotypicstrategies
(28to17)
-followerswerediscoveredwith
target-basedstrategies(83to30).
Swinney & Anthony NRDD, 10, 507, 2011
NME-newmolecularenEty
Iden4fica4onMMOA“pharmacologicalhotspot”
isrequiredforreduc4onist,engineeringapproach
Unmetmedical
need
advanceinclass
Molecular,
target-based
strategy
phenotypicassay
mechanis4c
empirical
iden4fytarget,
MMOAandnetworks
offirst-in-class
Targetisbiomarker
fordisease
Transla4onal
biomarkers
Clinicallyrelevant
thattranslatesto
humandisease
Screenwithlimited
mechanis4c
assump4ons-
firstinclass
‘pharmacologicalhotspot’
Swinney,CPT93,2992013
StrengthsofPhenotypic(PDD)andtarget(TDD)
complimenttheirrespec4veweaknesses.
WEAKNESS
STRENGTHS
TDD
Knowledgebased
PDD
Empirical
-structurebaseddesign
-PK/PDpredic4ons
-Pa4entselec4on
-System-based
-Iden4fica4onofMMOA
-Earlysafetyevalua4on
-Mostavailableknowledgeis
incomplete
-Notsystemsbased
-TargetselecEon
-IdenEficaEonofMMOA
Difficulttouseempirical
findingswith
-Structurebaseddesign
-PK/PDpredicEons
-PaEentselecEon
Howcannewinnova4vemedicinesbediscovered?
PrecisionmedicineIni4a4ve
Genotype
Target
X
Medicine
Pa4ent
MMOA,pharmacologicalhotspots
mechanis4cparadox
- the knowledge of mechanism (e.g. how a drug works) is very
helpfultodiscoverandpreciselyusemedicines
-theknowledgeavailableisrarelysufficientlycompletetoprovide
ablueprintfordiscoveryandini=aluseofthemedicines.
Takehomemessages
MolecularmechanismsofacEon(MMOAs)thatconnect
genotypetophenotypeareaprioridifficulttopredict
Empirical(phenotypic)approachestoidenEfyMMOAsand
correspondingleadmoleculesaremoresuccessfulforfirst-inclassmedicines
Ins4tuteforRareandNeglectedDiseaseDrugDiscovery
iRND3
Non-profit501c3drugdiscoveryorganiza'on
WellequippedlaboratoryMountainView,CA,USA
ExperiencedrugdiscoveryteamwithmanyyearsofPharmaexperience
www.irnd3.org
Mission
iRND3'smissionistodiscovernewmedicinesforrareandneglecteddiseases
Vision
-touElizeourunderstandingofhowsuccessfulnewmedicinesarediscoveredto
implementandexecutedrugdiscoverystrategiesthatsupplyourgrowingpipelineof
newcandidatemedicinesforrareandneglecteddiseases.
-toevolveaninnovaEve,sociallyresponsibleoperaEonalmodelforsuccessful
collaboraEonsbetweenthenon-profit,privateandpublictotranslatescienEfic
discoveriestoaconEnuoussourceofnewmedicines.