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Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson * GSK, Stevenage, UK *Current address – Stevenage Bioscience Catalyst 17th RSC/SCI Medicinal Chemistry Symposium Cambridge, UK. September 2013

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Page 1: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Enhancing molecule quality by combining fragments and early pharmacy input

Simon Hodgson*

GSK, Stevenage, UK

*Current address – Stevenage Bioscience Catalyst

17th RSC/SCI Medicinal Chemistry SymposiumCambridge, UK.  September 2013

Page 2: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Collaborative project between GSK and Astex

Gordon Saxty *Paul MortensonDavid NortonLee PagePhil DayCaroline RichardsonAnne CleasbyJoe CoyleRachel McMenaminDavid ReesChris MurrayJeff Yon

Simon Hodgson * Dave ClaphamKaren AffleckSimon TeagueEmma SherriffJon HutchinsonLinda RussellSorif UdinJoelle LeDon SomersAshley HancockHeather HobbsRobin CarrAndrew Leach * Co‐project leaders

Page 3: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Talk structure

• Background– Attrition

– Importance of Solubility

– DD approaches

• Application of FBDD and early pharm dev intervention ‐ PGDS example

Page 4: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Attrition – we can have an impact!

• Early example of how a major attrition factor of PK/ bioavailability changed 1991‐2000

• Early incorporation of DMPK reason for the improvement• But attrition challenges shifted further to clinical efficacy

Kola, Landis NRDD 2004

Page 5: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

The War on Attrition

• Pre‐clinical to Phase III success = 4.3% survival rate; ‘Phase II graveyard’• 4‐5% Improvement will double output 

• Caveat: clinical phase attrition is often multi‐factorial: ‘poor exposure’contributes to efficacy failure in Phase II

• Industry is moving from a ‘quantity’ to a ‘quality’ strategy

Data supplied by Phil Miller, Thomson Reuters© CMR International, a Thomson Reuters business 

Industry Success Rates & Causes of Attrition 2006‐10

Pharma’s problems: Paul et al, Nat. Rev. Drug Disc., 2010, 9, 203; Scannell et al, Nat. Rev. Drug Disc., 2012, 11, 191

Courtesy P.Leeson

Page 6: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Phase II Attrition: Pfizer Data 2005‐2009 (n=44)Levels of Confidence in 3 ‘Pillars’: 1) Exposure at target site of action; 2) Binding to target; 3) Pharmacological response

• Low confidence in exposure in 18/34 non‐progressing molecules: “cannot conclude mechanism tested adequately in 43% of cases”

• Compound quality issue: formulation; DMPK; dose prediction; safety margin.  Should be resolved prior to Phase II?

3 Pillars:  Morgan et al, Drug Discovery Today 2012, 17, 419‐424 

None or partially metn = 12

•12 failed to test mechanism•0 phase III starts

Exposure & Bindingn = 12

•5 tested mechanism•2 phase III starts

All metn = 14

• 14 tested mechanism• 12 achieved positive POC• 8 phase III starts

Binding & Pharmacologyn = 6

• 5 tested mechanism• 0 phase III starts

Pharmacological confidence

Expo

sure con

fiden

ce

LowLow

High

High

Courtesy P.Leeson

Page 7: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

What Do Medicinal Chemists Actually Make? 

• A 50‐year retrospective from J.Med. Chem• Mean properties for compounds appearing in JMC papers during 

the first 5 years of publication and in the most recent 5‐year period

W Walters et al VertexJ. Med. Chem. 2011, 54, 6405–6416

Page 8: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Probing the links between in vitro potency, ADMET and physicochemical parameters 

• Analysis using the ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compounds

• Key findings– oral drugs generally don’t have low nanomolar potency (50 nM on average); – many oral drugs have considerable off‐target activity– in vitro potency does not correlate strongly with the therapeutic dose. 

• These findings suggest that the perceived benefit of high in vitro potency may be negated by poorer ADMET properties 

• ‘Catch22’ – chasing low dose (to obviate DD issues) by high target affinity (and DD methods) made properties worse!

P.Gleeson, A.Hersey, D. Montanari, J.OveringtonNRDD 2011

Page 9: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Developability Classification System (DCS): for Formulation Development. 

Useful for Chemists to focus on!

• Importance of solubility, permeability and dose• Earlier BCS classification to DCS, uses FaSSIF solubility, and sub‐

divides class II further

J.Butler, J.Dressmann

Journal of Pharmaceutical Sciences, Vol. 99, 4940–4954 (2010)

Page 10: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

DCS 2BN=8

DCS 3N=25‐27

DCS 4N=4

DCS 2AN=17‐34

DCS 1N=50‐65

Top 121 oral prescription medicines by DCS

Dose/Intestinal solubility (mL)

J.Butler J.Dressmann

Journal of Pharmaceutical Sciences, Vol. 99, 4940–4954 (2010)

Page 11: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Despite a wide recognition of the importance of solubility, pipeline drugs are not optimal

• Current portfolio of pipeline development drugs aimed at oral administration in comparison to marketed drugs, shows a strong trend towards drug candidates with low aqueous solubility

• ~90% of pipeline drugs fall into BCS classes II & IV

http://www.americanpharmaceuticalreview.com/Featured‐Articles/135982‐The‐Innovator‐Pipeline‐Bioavailability‐Challenges‐and‐Advanced‐Oral‐Drug‐Delivery‐Opportunities/

Ralph Lipp. Amer. Pharmaceutical Review Apr 2013

Page 12: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Poor solubility impacts from early to late stage drug discovery

• Early Discovery– In vitro assays – inaccurate assessment of potency and 

variability– Low bioavailability

• Poor pre‐clinical efficacy

• Post Selection of Development Candidate– Inability to achieve pre‐clinical tox cover to support clinical 

studies– Poor clinical efficacy/ insufficient or variable exposure to test 

the mechanism– Formulation development cost and time increase

• For early clinical studies• Late stage attrition! Complex formulation development often delayed until after encouraging phase1/2

Page 13: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Approaches to addressing solubility

• Working with the Candidate– Salt formation might be enough– Particle size to increase dissolution rate– Complex formulation

• E.g Lipidic in capsule– Stabilised amorphous form

LatePass the problem on!

Page 14: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Approaches to addressing solubility

• Working with the Candidate– Salt formation might be enough– Particle size to increase dissolution rate– Complex formulation

• E.g Lipidic in capsule– Stabilised amorphous form

• Change the chemistry of the lead series– Pro‐drug the lead candidate– Structurally modify a poorly soluble series

LatePass the problem on!

Quite lateFurther LO resourceComplexity

Page 15: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Approaches to addressing solubility

• Working with the Candidate– Salt formation might be enough– Particle size to increase dissolution rate– Complex formulation

• E.g Lipidic in capsule– Stabilised amorphous form

• Change the chemistry of the lead series– Pro‐drug the lead candidate– Structurally modify a poorly soluble series

• Start in intrinsically more soluble chemical space !

LatePass the problem on!

Quite lateFurther LO resourceComplexity

Page 16: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Property comparison between leads derived from fragments vs. other approaches

Astex in‐house analysis comparing their fragment derived leads and hits with literature for same targets

C.Murray, M.Verdonk & D.ReesTIPS May 2012, Vol. 33, No. 5

P.Leeson,  S.St‐Gallay,NRDD 2011, 10, 749–765

Properties taken from patent literature of 18 companies.Astex (fragments) vs. the other companies shows reduced logP and MW

Page 17: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Influence of discovery strategies on properties of drug candidates – not clear on solubility

• Analysis based on general literature, very diverse set • Fragments vs. HTS : Solubility higher for hits, but not leads

G.Keserü, Makara,  NRDD 2009

Page 18: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Example with Haematopoietic Prostaglandin D2 Synthase (PGDS)

Page 19: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

PGDS in the eicosanaoid pathway• PGDS inhibition could impact on a range of lipid mediators & receptors 

potentially important in allergic and inflammatory diseases 

Page 20: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Prostaglandin lipid pathways ‐ PGDS

Page 21: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Example PGDS inhibitors

• Typified by lipophilic Biaryl groups in the active site

HQL79 Pfizer Sanofi

US2008/0146569A1 WO2008/121670A1Matsushita, N. Jpn. J. Pharmacol. 1998,78,,1–10 & 11–22

N

F

O NH

N

F

FF

N

N N

O NHN

F

O

N

N NN

NH

N

F

O NH

N

NN N

N

1 232A

Page 22: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

PGDS ‐Med Chem challenge and approach

• PGDS– binds lipid substrate– example inhibitors generally quite lipophilic

• Known inhibitors bind in lipophilic enzyme active site (Xray)

• Trial screening set on PGDS showed strong potency/logPcorrelation

• Hypothesis Structurally driven, fragment approach to increase chances for low 

MWt leads with good solubility properties

• Early use of pharmacy to measure progress, decision making

Page 23: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

The Astex Pyramid Approach

X‐Ray

INTEGRATED BIOPHYSICAL SCREENING

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

-6

-4

-2

0

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

0.10 20 40 60 80 100

Time (min)

µcal

/sec

Molar Ratio

kcal

/mol

e of

inje

ctan

t

305 310 315 320 325 330 335

1x105

2x105

3x105

4x105

5x105

Fluo

resc

ence

(a.u

.)

Temperature (K)

NMR

Tm

ITC

Astex PYRAMID™Screening

AstexProprietaryFragment Library

Targeted & Virtual ScreeningFragmentSets

STRUCTURE‐LED OPTIMISATION

Fragment‐to‐Candidate Chemistry

Astex Rule of 3™

FRAGMENT SELECTION

NH

N

ONH2

Cl

NN

NN

N

N NH2ClN NH2

N

NNH2

ClOH

NH

NH

NH2

O

OCl

NN

NH

S

Page 24: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Pharm Dev work to support selection of the Development Candidate

• Typically conducted on candidate/pre candidate– Full pH/solubility profile

– Full pH/solution state stability profile

– Solid state form• XRPD, DSC, TGA, GVS

– Solid state stability 

– If required version and form assessment

– Formulation recommendations for formal toxicology studies and early clinical studies

Page 25: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Introduction of earlier Property Intervention for PGDS (after CLND)

• CLND solubility to triage compounds– High Throughput (1,000’s per week)– Screen out insoluble compounds to aid SAR– Precipitation from DMSO solution

• Early Pharm Dev intervention– Low throughput <10 per week– Solubility from solid in Physiologically relevant fluids

• Simulated Gastric Fluid (pH=1.6), Fed State Simulated Intestinal Fluid (pH=6.5), Fasted State Simulated Intestinal Fluid (pH=6.5), Water

– Solution state stability assessment• Chemical and Photostability

– Investigated Pharm Dev properties of early compounds• Identify solubility or stability challenge in series allowing chemistry effort to be 

redirected to more promising areas• Inadequate PhysChem properties in the light of predicted dose could lead to 

recommendation not to progress 

Page 26: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

PGDS Progression Profiles

ValidatedHits

DevelopmentCandidate

Confirmed Binding Mode (Xray)LE >0.3

Fragment OptH2L LEAD OPT

Small number seriesfor LO

‘N’ clusters

Novel seriesEnzyme/Cell  7‐8LE/LLE >0.3Stability/Solubility ProfileOral activity

Enzyme/Cell 6‐ 7LE/LLE 0.4

TractableppbCLND Sol(p450; X‐screen)

Multiple chemical series

Commit to LO

Page 27: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Fragment screen results

• Biophysical screening

• 76 validated hits– Confirmed by X‐ray

– Measurable activity in fluorescence polarisation binding assay

• IC50 >1000uM ‐ 0.5uM

• LE 0.26 – 0.52 kcal/mol/HAC

• LLEAT*0.23 – 0.50 kcal/mol/HAC

• => grouped into 10 clusters

* LLEAT, P.Mortenson, C.Murray, J. Comp‐Aided Mol Design, 2011, 25, 663

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Cluster 1 – noteworthy example

• 4 is weak but efficient inhibitor• Small perturbation of protein• Induces disruption of intramol H‐bond of 

Tyr152 phenol and Asp96 acid• Polar interactions in active site pocket• Fragment optimisation to 5,  gave >10‐fold 

potency increase

4IC50  =8.5uMLE 0.46; LLEAT 0.36

X‐ray Fragment Hit

5IC50 = 0.5uMLE 0.57; LLEAT 0.44

Fragment Optimisation

>10 fold

Page 29: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Cluster 2 – noteworthy example

• Fragment 6 also shows similar Asp96 & Try152 shift

• Polar interactions in active site pocket again

• Xray overlays show different binding of Biaryl in 6 compared with published Biaryl ligand 2

• CN overlays with carbonyl in 2

652% inhib @30uMLE ~0.44; LLEAT ~0.39

X‐ray Fragment Hit

Page 30: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Cluster 2 – fragment optimisation

• 7 has lower MWt, higher LE/LLE.  Pyridyl‐N  H‐bond to water• Filling pocket more optimally with c‐propyl• 8 occupies same binding as 6, but potency increased, high 

efficiency

652% inhib @30uMLE ~0.44; LLEAT ~0.39

X‐ray Fragment Hit

758% inhib @100uMLE ~0.50; LLEAT ~0.50

Analogue Screening

8IC50 = 17uMLE 0.46; LLEAT 0.45

Fragment Optimisation

Page 31: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Cluster 2 – fragment growth and optimisation to orally active inhibitor

• X‐ray structural analysis suggested better growth vector opportunities with fragment 8.   Target between 5‐ and 6‐pyridyl position

• 400 fold potency increase with 9. High LE/LLE maintained.• 9 too polar (clogP 0.7) !• LogP increased to attain good cell potency in 10

clogP 1.8; MW 337

8IC50 = 17uMLE 0.46; LLEAT 0.45

Fragment Optimisation

400 fold

10: AT24111/GSK296124A66% Inhibn. @10nMLE ~0.46; LLEAT ~0.45

Orally Active Lead

Page 32: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

FBDD lead 10 has good solubility in a range of physiologically relevant media

pIC50 7.9 *8.3 7.7 8.8

LE ;  LLE 0.43; 0.45 0.37;  0.38 0.44;  0.39

MW ; clogP 337;  1.8 381;  2.2 361; 3.3

Water (ug/ml) 52 (=150uM)

*1.2 17 4

SGF  (ug/ml) 885 49 203

FeSSIF (ug/ml) 136 44 <1

FaSSIF (ug/ml) 109 31 5

SGF = Simulated gastric fluid (pH 1.6)FeSSIF = Fed simulated intestinal fluid (pH 6.5)FasSSIF = Fasted simulated intestinal fluid (pH 6.5) * C. Carron et al, ACS Med. Chem. Lett. 2010, 1, 59–63

10: AT24111/GSK296124A

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DCS 2BN=8

DCS 3N=25‐27

DCS 4N=4

DCS 2AN=17‐34

DCS 1N=50‐65

Top 121 oral prescription medicines by DCS

Dose/Intestinal solubility (mL)

J.Butler J.Dressmann

Journal of Pharmaceutical Sciences, Vol. 99, 4940–4954 (2010)

Page 34: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

FBDD lead 10 is orally bioavailable using a simple aqueous formulation, and inhibits PGDS in vivo

Inhibition of PGD2 in peritoneal cavity after oral dosing at 30mg/kg to mice

PK Parameter Compound 10

CLb (mL/min/kg) 33

T½ (h) 2.2

Vss (L/kg) 2.8

Tmax (p.o.) (h) 0.5

Cmax (p.o.) (ng/mL) 196

AUC0‐inf (ng.h/mL) 295

F (%) 19

fub 5.5%

Rat PK, from oral/IV dosing in aqueous formulation

Dosing: 1mg/kg IV; 3mg/kg poDrug conc in blood

All animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals

Page 35: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

FBDD approach identified several series with favourable properties

• With FBDD approach, strong focus on LE/LLE and upper limit of MWt• Potencies </= 10nM achieved with MWt 300‐400• Additional solubility dimension => highlights further series strengths

MW vs potency Solubility vs potency

Page 36: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Conclusions• Solubility is a key parameter in drug development

– Impact on bioavailability, dose, complexity of formulation, Drug Development cost, time, attrition (late failure!)

• Good solubility property has ‘suffered’ due to focus on high target affinity, compound library properties, and DD approach. Pipeline drugs carry risk.

• Fragment based drug discovery approach successfully generated multiple series with good properties in lipophilic target – PGDS

• Identification of novel protein movement/H‐bonding disruption, & novel fragment polar binding interactions in lipophilic active site

• X‐ray guided fragment optimisation, optimal vector growth, and early pharmacy input combined to give a PGDS inhibitor series with favourable properties (LE/LLE, MWt, logP, Solubility and DCS class )

Page 37: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Conclusions• Solubility is a key parameter in drug development

– Impact on bioavailability, dose, complexity of formulation, Drug Development cost, time, attrition (late failure!)

• Good solubility property has ‘suffered’ due to focus on high target affinity, compound library properties, and DD approach

• Fragment based drug discovery approach successfully generated multiple series with good properties in lipophilic target – PGDS

• Identification of novel protein movement/H‐bonding disruption, & novel fragment polar binding interactions in lipophilic active site

• X‐ray guided fragment optimisation, optimal vector growth, and early pharmacy input combined to give a PGDS inhibitor series with favourable properties (LE/LLE, sol, MWt, logP)

• Orally active from simple aqueous formulation – ‘proof of the pudding’

Page 38: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current

Thank You

Contact Details

Dr Simon Hodgson Hodgson Pharma [email protected]

Page 39: Enhancing molecule quality by combining fragments and ... · Enhancing molecule quality by combining fragments and early pharmacy input Simon Hodgson* GSK, Stevenage, UK *Current