Applications of Fragment Based Approaches

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Applications of Fragment Based Approaches Ben Davis Vernalis R&D, Cambridge UK b.davis@vernalis.com 1

Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 2

Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 3

creening fragment libraries Different experimental approaches have different strengths and limitations Fragments MW 110-250 X-Ray crystallography MR PR Enzyme assays caffolds MW 200-300 ITC Lead Compounds 10mM 1mM 100µM 10µM 1µM Affinity 4

creening - urface Plasmon Resonance (PR) Technique which detects change in molecular weight Immobilise receptor on surface (direct mode) Flow putative ligand over surface bserve change in refractive index (function of mass on surface) btain k on, k off, K d (or K i in indirect mode) Dissociation Resonance ignal (RU) Association Kinetics Concentration Time (s) 5

creening - PR Bind receptor to chip surface Generic is-tag attachment protocol Experimental setup creen individual compounds Detect direct binding ear change and sensible sensorgram Learn with experience signs of misbehaviour P90: a drugable target most MR hits also found by PR 9 hits in common 1 non competitive 1 failed crystallography 2 MR hits missed by PR Also some false positives 6

PR harder target PPI example, similar setup to P90 Direct binding experiment 29 confirmed MR hits (1D methods and 15 QC) 9 hits did not show binding by PR 14 well behaved hits 6 exhibited odd binding 1:1 1:1 7

creening fragment libraries MR remains gold standard ignificant protein demands PR good choice o MR access Low amounts of protein Crystallography Requires appropriate crystal form Validate hits with alternative method prior to xtal 8

The eeds process tructural Exploitation of Experimental Drug tartpoints ubbard et al (2007), Curr Topics Med Chem, 7, 1568 Target its Validation creening 2 Drug? Design, Build & Test tructure Determination 9

creening - MR Competitive binding experiment Target + fragments Target + fragments + competitor ligand n-the-fly QC MR experiments observe fragment only if binding as competitor displaced the fragment? => pecific binding 1-10% hit rate for Fragments 10

Experiment 1D a b c Competitor - + TD - + I = f ( ) obs P bound LGY - + I obs = f ( P P ) bound free CPMG - + I = f ( ) obs P free Compound b binds and is displaced by competitor in all experiments 11

The eeds process - results A good library Fit for purpose Drug space Chemistry friendly Robust detection MR methods Ligand based screening X-ray crystallography TX with soakable form PR methods igh Concentration creening DF Thermal melt ass 1 hits rates 8% 7% 6% 5% 4% 3% 2% 1% 0% eeds hit rate vs Drugability 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 eeds drug space coverage Dscore Known 72% ovel 28% 12

Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 13

Characterising Fragments QC EY experiments Backbone dynamics TD buildups PR ITC X-ray Primary method for determining structures of bound fragments 14

Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 15

PDPK1 eeds screen Relatively novel target (2003) in hot PI3K-pathway erine/threonine kinase Library of ~ 1400 compounds screened by MR Competition step UC-01 nm ligand, binds in ATP site > 60 competitive eeds identified Range of distinct chemical classes identified ovelty & tractability 16

PDPK1 merging fragments Emphasising D-A-D binding motif to kinase hinge backbone 7µM in Chk1 3µM in PDPK1 tructure in PDPK1 tructure bound to Chk1 used to design minimal scaffold Agouron Chk1 inhibitor tructure in PDPK1 17

PDPK1 merging fragments 49336 180µM 48319 3µM tructure bound to Chk1 used to design minimal scaffold eeds identified by MR that competitively bind to PDPK1 active site. >60 eeds identified structures determined for >20. 49537 150µM Agouron Chk1 inhibitor 18

PDPK1 merging fragments 2 ewcastle CDK2 inhibitor (80nM) 53167 200nM in PDK1 49336 180µM ide chain occupies pocket in hinge cleft find compounds containing eed and hydrophobic side chain 48319 3µM tructure bound to Chk1 used to design minimal scaffold eeds identified by MR that competitively bind to PDPK1 active site. >60 eeds identified structures determined for >20. 49537 150µM Agouron Chk1 inhibitor 19

PDPK1 merging fragments 2 ewcastle CDK2 inhibitor 54525 7µM 53167 200nM 49336 180µM rcat 48319 3µM tructure bound to Chk1 used to design minimal scaffold eeds identified by MR that competitively bind to PDPK1 active site. >60 eeds identified structures determined for >20. rcat catalogue of available compounds, JCIC, 44 643 49537 150µM Agouron Chk1 inhibitor 20

PDPK1 merging fragments 2 ewcastle CDK2 inhibitor 2 81903 1µM 53167 200nM 49336 180µM Chemistry around side chains to explore affinity and solubility 48319 3µM tructure bound to Chk1 used to design minimal scaffold eeds identified by MR that competitively bind to PDPK1 active site. >60 eeds identified structures determined for >20. 49537 150µM Agouron Chk1 inhibitor 21

PDPK1 merging fragments 2 ewcastle CDK2 inhibitor 2 81903 1µM tructures of compounds bound to PDPK1 53167 200nM 49336 180µM 48319 3µM tructure bound to Chk1 used to design minimal scaffold eeds identified by MR that competitively bind to PDPK1 active site. >60 eeds identified structures determined for >20. 49537 150µM Agouron Chk1 inhibitor 22

PDPK1 merging fragments 2 ewcastle CDK2 inhibitor 2 81903 1µM ix months from hit ID to novel 90nM lead compound - 2 chemists 53167 200nM 49336 180µM 48319 3µM tructure bound to Chk1 used to design minimal scaffold eeds identified by MR that competitively bind to PDPK1 active site. >60 eeds identified structures determined for >20. 90nM 49537 150µM Agouron Chk1 inhibitor 23

PDPK1 lead generation eries optimisation PDPK1 IC 50 = 15nM elective vs several important kinases Potent on cells; CT116 GI 50 = 80nM Also active on a wide cancer panel Appropriate PD marker changes seen in vivo 24

sp90: eeds screen sp90 a chaperone protein crucial for cancer cells terminal domain has ATPase activity structure determined FBLD programme began in early 2002 - screened library of 729 fragments by MR 17 fragments identified Crystal structures determined for most fragments binding to sp90 Adenine Amide Resorcinol 25

sp90: Combining it id strategies 2 2 VER-26753 FP IC 50 =350µM VER-41113 FP IC 50 =1.56µM eeds its: Include eight aminotriazines or aminopyrimidine hits, - all crystallised Virtual creening its 2 2 2 2 VER-26734 FP IC 50 >5mM Me Et VER-4561626 FP IC 50 =0.9µM

sp90: Combining it id strategies 2 VER-26753 FP IC 50 =350µM 2 VER-48400 FP IC 50 =20µM VER-41113 FP IC 50 =1.56µM 2 Evolve fragments D93 G97 K58 2 2 2 VER-26734 FP IC 50 >5mM Me 2 VER-52959 FP IC 50 =535µM F138 L107 2 Et VER-4561627 FP IC 50 =0.9µM

sp90: Combining it id strategies 2 VER-26753 FP IC 50 =350µM 2 VER-48400 FP IC 50 =20µM VER-41113 FP IC 50 =1.56µM 2 From structures: merge features into new fragment 2 2 2 VER-26734 FP IC 50 >5mM Me 2 VER-52959 FP IC 50 =535µM 2 Et VER-4561628 FP IC 50 =0.9µM

sp90: Combining it id strategies 2 VER-26753 FP IC 50 =350µM 2 VER-48400 FP IC 50 =20µM VER-41113 FP IC 50 =1.56µM 2 Designed fragment: combination of fragment and virtual screening hit 2 2 2 D93 G97 K58 L107 VER-53116 FP IC 50 =1250µM F138 2 2 2 VER-26734 FP IC 50 >5mM Me 2 VER-52959 FP IC 50 =535µM ovelty Tractability Removed metabolic liability 2 Et VER-4561629 FP IC 50 =0.9µM

sp90: Combining it id strategies 2 VER-26753 FP IC 50 =350µM 2 VER-48400 FP IC 50 =20µM VP-AUY922 VER-41113 FP IC 50 =1.56µM 2 ub-micromolar cell activity 2 2 VER-26734 FP IC 50 >5mM Me 2 VER-52959 FP IC 50 =535µM VER-55192 FP IC 50 =0.230µM CT116 GI 50 =0.82µM BT474 GI 50 =0.32µM VER-53116 FP IC 50 =1250µM 2 2 Et VER-4561630 FP IC 50 =0.9µM 2

sp90: Combining it id strategies 2 VER-26753 FP IC 50 =350µM 2 VER-48400 FP IC 50 =20µM VP-AUY922 VER-41113 FP IC 50 =1.56µM 2 ub-micromolar cell activity 2 2 VER-26734 FP IC 50 >5mM Me 2 VER-52959 FP IC 50 =535µM VER-55192 FP IC 50 =0.230µM CT116 GI 50 =0.82µM BT474 GI 50 =0.32µM 2 2 Et VER-4561631 FP IC 50 =0.9µM 2

sp90: Combining it id strategies 2 VER-26753 FP IC 50 =350µM 2 VER-48400 FP IC 50 =20µM VP-AUY922 VER-41113 FP IC 50 =1.56µM 2 Cell potency breakthrough and oral efficacy 2 VER-26734 FP IC 50 >5mM Me 2 VER-52959 FP IC 50 =535µM 2 Et 2 VER-82160 FP IC 50 =0.056µM CT116 GI 50 =0.187µM BT474 GI 50 =0.059µM 2 2 Et VER-4561632 FP IC 50 =0.9µM 2

sp90: Combining it id strategies 2 VER-26753 FP IC 50 =350µM 2 VER-48400 FP IC 50 =20µM VP-AUY922 VER-41113 FP IC 50 =1.56µM 2 VP-BEP800 selected as preclinical candidate 2 VER-26734 FP IC 50 >5mM Me 2 VER-52959 FP IC 50 =535µM 2 VER-82576 VP-BEP800 FP IC 50 =0.058µM CT116 GI 50 =0.161µM BT474 GI 50 =0.057µM 2 2 Et VER-4561633 FP IC 50 =0.9µM 2

Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 34

Fragments main points Finding fragments that bind is relatively easy For well behaved active sites 5-10% hit rates Even for challenging protein-protein sites 1-4% Fragments are just small, weak hits mall number of compounds sample large chemical diversity Design of library crucial Properties, diversity, vectors Challenge is deciding what to do with the fragments Fragments provide inspiration & guidance for design of novel compounds that may require ambitious chemistry Critical is integration of structure, modelling and chemistry Doesn t necessarily speed up the hit discovery process Major benefit is choice in discovery umber and quality of fragments ovelty of interactions & scaffolds 35

What s next for fragments? Big pharma adopting fragments alongside T Designing new fragments Three dimensional diversity Vectors, shape, functionality distribution Decisions, decisions - which fragments to evolve? o many hits 100 for some binding sites Fragments in absence of crystal structure Fragments are small hits - need AR for medicinal chemistry eed methods to quantify binding in 100µM 10mM range tructure gives chemistry direction before on scale in assay 36

Acknowledgements eeds Rod ubbard, eather immonite, Christophe Fromont, tuart Ray, Lindsey Terry & many others Crystallography & PR James Murray, atalia Mattasova, Pawel Dokurno, Lisa Wright, Alan urgenor, David Robinson Initial eeds library design icolas Baurin & many medicinal chemists at Vernalis eeds library design and analysis Ijen Chen PDPK1 Lee Walmsley, Jon Moore, Chris Torrance, Joanne Wayne sp90 Martin Drysdale, Xavier Barril, Brian Dymock, Andy Massey, and many other team members 37

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