Applications of Fragment Based Approaches
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1 Applications of Fragment Based Approaches Ben Davis Vernalis R&D, Cambridge UK 1
2 Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 2
3 Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 3
4 creening fragment libraries Different experimental approaches have different strengths and limitations Fragments MW X-Ray crystallography MR PR Enzyme assays caffolds MW ITC Lead Compounds 10mM 1mM 100µM 10µM 1µM Affinity 4
5 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
6 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
7 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
8 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
9 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
10 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
11 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
12 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 eeds drug space coverage Dscore Known 72% ovel 28% 12
13 Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 13
14 Characterising Fragments QC EY experiments Backbone dynamics TD buildups PR ITC X-ray Primary method for determining structures of bound fragments 14
15 Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 15
16 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
17 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
18 PDPK1 merging fragments µM µM 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 > µM Agouron Chk1 inhibitor 18
19 PDPK1 merging fragments 2 ewcastle CDK2 inhibitor (80nM) nM in PDK µM ide chain occupies pocket in hinge cleft find compounds containing eed and hydrophobic side chain µM 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 > µM Agouron Chk1 inhibitor 19
20 PDPK1 merging fragments 2 ewcastle CDK2 inhibitor µM nM µM rcat µM 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, µM Agouron Chk1 inhibitor 20
21 PDPK1 merging fragments 2 ewcastle CDK2 inhibitor µM nM µM Chemistry around side chains to explore affinity and solubility µM 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 > µM Agouron Chk1 inhibitor 21
22 PDPK1 merging fragments 2 ewcastle CDK2 inhibitor µM tructures of compounds bound to PDPK nM µM µM 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 > µM Agouron Chk1 inhibitor 22
23 PDPK1 merging fragments 2 ewcastle CDK2 inhibitor µM ix months from hit ID to novel 90nM lead compound - 2 chemists nM µM µM 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 µM Agouron Chk1 inhibitor 23
24 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
25 sp90: eeds screen sp90 a chaperone protein crucial for cancer cells terminal domain has ATPase activity structure determined FBLD programme began in early screened library of 729 fragments by MR 17 fragments identified Crystal structures determined for most fragments binding to sp90 Adenine Amide Resorcinol 25
26 sp90: Combining it id strategies 2 2 VER FP IC 50 =350µM VER FP IC 50 =1.56µM eeds its: Include eight aminotriazines or aminopyrimidine hits, - all crystallised Virtual creening its VER FP IC 50 >5mM Me Et VER FP IC 50 =0.9µM
27 sp90: Combining it id strategies 2 VER FP IC 50 =350µM 2 VER FP IC 50 =20µM VER FP IC 50 =1.56µM 2 Evolve fragments D93 G97 K VER FP IC 50 >5mM Me 2 VER FP IC 50 =535µM F138 L107 2 Et VER FP IC 50 =0.9µM
28 sp90: Combining it id strategies 2 VER FP IC 50 =350µM 2 VER FP IC 50 =20µM VER FP IC 50 =1.56µM 2 From structures: merge features into new fragment VER FP IC 50 >5mM Me 2 VER FP IC 50 =535µM 2 Et VER FP IC 50 =0.9µM
29 sp90: Combining it id strategies 2 VER FP IC 50 =350µM 2 VER FP IC 50 =20µM VER FP IC 50 =1.56µM 2 Designed fragment: combination of fragment and virtual screening hit D93 G97 K58 L107 VER FP IC 50 =1250µM F VER FP IC 50 >5mM Me 2 VER FP IC 50 =535µM ovelty Tractability Removed metabolic liability 2 Et VER FP IC 50 =0.9µM
30 sp90: Combining it id strategies 2 VER FP IC 50 =350µM 2 VER FP IC 50 =20µM VP-AUY922 VER FP IC 50 =1.56µM 2 ub-micromolar cell activity 2 2 VER FP IC 50 >5mM Me 2 VER FP IC 50 =535µM VER FP IC 50 =0.230µM CT116 GI 50 =0.82µM BT474 GI 50 =0.32µM VER FP IC 50 =1250µM 2 2 Et VER FP IC 50 =0.9µM 2
31 sp90: Combining it id strategies 2 VER FP IC 50 =350µM 2 VER FP IC 50 =20µM VP-AUY922 VER FP IC 50 =1.56µM 2 ub-micromolar cell activity 2 2 VER FP IC 50 >5mM Me 2 VER FP IC 50 =535µM VER FP IC 50 =0.230µM CT116 GI 50 =0.82µM BT474 GI 50 =0.32µM 2 2 Et VER FP IC 50 =0.9µM 2
32 sp90: Combining it id strategies 2 VER FP IC 50 =350µM 2 VER FP IC 50 =20µM VP-AUY922 VER FP IC 50 =1.56µM 2 Cell potency breakthrough and oral efficacy 2 VER FP IC 50 >5mM Me 2 VER FP IC 50 =535µM 2 Et 2 VER FP IC 50 =0.056µM CT116 GI 50 =0.187µM BT474 GI 50 =0.059µM 2 2 Et VER FP IC 50 =0.9µM 2
33 sp90: Combining it id strategies 2 VER FP IC 50 =350µM 2 VER FP IC 50 =20µM VP-AUY922 VER FP IC 50 =1.56µM 2 VP-BEP800 selected as preclinical candidate 2 VER FP IC 50 >5mM Me 2 VER FP IC 50 =535µM 2 VER VP-BEP800 FP IC 50 =0.058µM CT116 GI 50 =0.161µM BT474 GI 50 =0.057µM 2 2 Et VER FP IC 50 =0.9µM 2
34 Applications of Fragment Based Approaches creening fragment libraries Techniques Vernalis eeds approach Characterising binding tructure, thermodynamics and kinetics eeds Applications PDPK1 sp90 Conclusions 34
35 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
36 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
37 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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