The Interplay of Kinase Broad Profiling and Phenotypic Screening. Edgar Jacoby DiscoverX Webinar December, 7, 2016
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1 The Interplay of Kinase Broad Profiling and Phenotypic Screening Edgar Jacoby DiscoverX Webinar December, 7, 2016
2 Agenda Broad Profiling as a Discovery Strategy The World is the Laboratory for Phenotypic Screening : DSTT OpenPhacts Computational Protocols in Phenotypic Screening DiscoverX
3 A discovery strategy based on broad profiling Capitalize on existing chemical assets Prioritize biochemical vs.cell-based assay development Kinase Broad Profiling Hits for new projects Link to chemogenomics and systems approach Probe compounds - Target ID and Validation Crizotinib JNJB DiscoverX
4 Available kinase profiling technologies 2013 Various kinase profiling panels are available DiscoverX (Ambit) 464 assays, 396 unique wt kinases Millipore (Upstate) 240 wt kinases Invitrogen (LifeTech.) 319 inc mutants Dundee DSTT (MRC) 140+ Carna 307 incl mutants Signalchem ~400 kinases Caliper - ~200 kinases React. Biol. Corp. 440 kinase assays Nanosyn 290 kinases ProQinase 374 kinases Many considerations: constructs, assay technology, assay conditions, kinase and ATP concentration, kinase substrate selection, mutants, Crizotinib JNJB DiscoverX
5 DiscoverX KINOMEscan Platform Slide from DiscoverX Crizotinib JNJB DiscoverX
6 Compilation of kinase inhibitor basis set ~ 77 K compounds from 40 Janssen kinase projects Medicinal Chemistry Selection 3K set 11K set 77K set 3368 Kinase Inhibitors for Profiling Diversity of selected compounds in SPE map Crizotinib JNJB DiscoverX
7 Kinome coverage depends on selection criteria S65= 0.10 S65= 0.05 S65= Displacement Efficacy >= 95% and S65 <= 5% S65 : Fraction of kinases with Displacement Efficacy > 65% at 1 um Further extension rate : kinases / 1000 compounds Crizotinib JNJB DiscoverX
8 Most selective compounds confirm poorly Confirmation statistics grouped by selectivity (S65) and efficacy(de) Results : - 51% confirmation rate - Compounds with higher efficacy have higher validation rates : as expected - Promiscuous compounds have higher validation rates : not expected Crizotinib JNJB DiscoverX
9 Broad coverage of major kinase subfamilies with potent and selective compounds Analysis of total 11K set 5500 Cpds DiscoveRx : KDs 6800 Cpds Millipore : IC50s Branches not covered at 10 nm are covered at 100 nm Power law: For many kinases only 1 hit Data in 3DX PDS Crizotinib JNJB DiscoverX
10 Where are the opportunities for Janssen? Janssen : Kinases with Cpds IC50/KD <= 100 nm S65 <= 0.05 : 257 Eidogen Sertanty Janssen 11K set 96 Eidogen : Kinases with more than 10 Cpds IC50/KD <= 100 nm : Kinases which are from medicinal chemistry perspective little/not explored but are covered by Janssen compounds Datasheet available from KP team Crizotinib JNJB DiscoverX
11 Broad screening positively impacts kinase project teams Identification of potential chemical starting points Confirms hit identified in HTS Tool compounds for assays Prioritization of compounds from HTS based on selectivity Prioritization of assay format for HTS Validation/Devalidation of target Ideas for covalent designs Initiation of new projects DiscoverX
12 DiscoverX
13 The world is the laboratory for phenotypic screening Janssen collaborated with the Dundee DSTT consortium for phenotypic screening of selective and potent kinase inhibitors DSTT biology expertise on protein phosphorylation is very broad and enables a complementary chemical biology approach to jump start new projects Selected examples include: Lab Karim Labib : Regulation of chromosome replication Lab Carol Mackintosh : Regulation of proteins Lab Ian Ganley : Mitochondrial turn-over Lab John Rouse : DNA repair Lab Greg Findlay : Control of ES cell pluripotency DiscoverX
14 Hits Identified for Control of Pluripotency mesc model system Differentiating Control JAKi FGFRi Pluripotent FGFR LIF-JAK Naïve pluripotency Nanog+ Klf4+ Dnmt3b- Primed pluripotency Nanog- Klf4- Dnmt3b+ Nanog/Dnmt3b ratio mesc priming FGFR inhibitors labeled red Lab Greg Findlay DiscoverX
15 Signature Analysis Primary Activity Matrix Binary Activity Matrix Applying an Activity Threshold of 50% at 1 um Compound Concentration SIGNATURE Summation of Hits per kinase DiscoverX
16 Hits Identified Driving Naive State JNJB TargetCount 75 TargetCount 50 Upst_FGFR1_h_ATP10 Effect_at_1_uM Upst_FGFR2_h_ATP10 Effect_at_1_uM Upst_FGFR3_h_ATP10 Effect_at_1_uM Upst_Flt4_h_ATP10 Effect_at_1_uM Upst_Flt1_h_ATP10 Effect_at_1_uM Upst_FGFR4_h_ATP10 Effect_at_1_uM Upst_Ret_h_ATP10 Effect_at_1_uM Upst_Lyn_h_ATP10 Effect_at_1_uM 8 14 Upst_Fms_h_ATP10 Effect_at_1_uM 7 14 Upst_Arg_h_ATP10 Effect_at_1_uM 3 3 Upst_EphA1_h_ATP10 Effect_at_1_uM 3 8 Upst_Hck_h_ATP10 Effect_at_1_uM 3 7 Upst_KDR_h_ATP10 Effect_at_1_uM 3 16 Upst_Abl_h_ATP10 Effect_at_1_uM 2 4 Upst_Aurora_B_h_ATP10 Effect_at_1_uM 2 4 Upst_EphA2_h_ATP10 Effect_at_1_uM 2 2 Upst_Lck_h_activated_ATP10 Effect_at_1_u 2 4 Upst_Lck_h_ATP10 Effect_at_1_uM 2 8 Upst_Tie2_h_ATP10 Effect_at_1_uM 2 4 Upst_TrkA_h_ATP10 Effect_at_1_uM 2 2 Upst_Yes_h_ATP10 Effect_at_1_uM 2 7 JNJB TargetCount-75 TargetCount-50 FGFR1_1uM FGFR2_1uM FGFR3_1uM FGFR4_1uM CSF1R_1uM FLT4_1uM EPHB6_1uM TIE1_1uM RET_1uM FLT1_1uM VEGFR2_1uM LCK_1uM 9 25 PRKR_1uM 7 19 BLK_1uM 6 14 DDR1_1uM 6 8 MAP3K2_1uM 4 7 MAP3K3_1uM 3 3 PDGFRB_1uM 3 12 NEK1_1uM 2 4 RIPK2_1uM 2 17 Lab Greg Findlay DiscoverX
17 Hits Identified Driving Primed State JNJB TargetCount-75 TargetCount-50 Upst_MELK_h_ATP10 Effect_at_1_uM 5 5 Upst_Flt3_h_ATP10 Effect_at_1_uM 4 4 Upst_TrkB_h_ATP10 Effect_at_1_uM 3 3 Upst_TrkA_h_ATP10 Effect_at_1_uM 2 4 Upst_Flt1_h_ATP10 Effect_at_1_uM 1 2 Upst_Flt4_h_ATP10 Effect_at_1_uM 1 2 Upst_GCK_h_ATP10 Effect_at_1_uM 1 2 Upst_CK2_h_ATP10 Effect_at_1_uM 1 1 Upst_CK2alpha2_h_ATP10 Effect_at_1_uM 1 1 Upst_c_RAF_h_ATP10 Effect_at_1_uM 1 1 Upst_eEF_2K_h_ATP10 Effect_at_1_uM 1 1 Upst_Fgr_h_ATP10 Effect_at_1_uM 1 1 Upst_Haspin_h_ATP10 Effect_at_1_uM 1 1 Upst_IRAK1_h_ATP10 Effect_at_1_uM 1 1 Upst_IRAK4_h_ATP10 Effect_at_1_uM 1 1 Upst_ITK_h_ATP10 Effect_at_1_uM 1 1 Upst_Lyn_h_ATP10 Effect_at_1_uM 1 1 Upst_Ros_h_ATP10 Effect_at_1_uM 1 1 Upst_Yes_h_ATP10 Effect_at_1_uM 1 1 JNJB TargetCount 75 TargetCount 50 FLT3_1uM 4 4 HASPIN_1uM 4 4 KIT_1uM 4 5 CSF1R_1uM 3 5 DDR1_1uM 3 5 JNK1_1uM 3 6 MELK_1uM 3 4 PDGFRB_1uM 3 5 BUB1_1uM 2 2 CLK1_1uM 2 4 CLK2_1uM 2 3 CLK4_1uM 2 4 DYRK1A_1uM 2 2 DYRK1B_1uM 2 3 DYRK2_1uM 2 3 GAK_1uM 2 2 JAK2(JH1domain_cata 2 2 JNK3_1uM 2 5 LOK_1uM 2 2 MEK5_1uM 2 4 PDGFRA_1uM 2 4 ROCK1_1uM 2 4 ROCK2_1uM 2 2 TRKC_1uM 2 2 TYK2(JH2domain_pse 2 2 YSK4_1uM 2 3 Lab Greg Findlay DiscoverX
18 Therapeutic Applications of Stemness Biology Cancer biology Evaluate the relevance of inducing differentiation of cancer cells by using compounds which push towards differentiated states. Regenerative medicine Rationale of usage of kinase inhibitors is to reversibly alter the transcriptional landscape of pluripotent stem cells (PSCs) Ex vivo reprogramming of PSCs followed by directed differentiation towards specialized cell types Potential applications of differentiated PSCs: Alzheimer s (Neuronal differentiation) Diabetes (Pancreatic differentiation) Cancer (Haematopoetic differentiation) DiscoverX
19 6 OpenPhacts Computational Protocols to Know the Knowns Protocol 1 : ChEBI/ChEMBL Annotation and Classification Protocol 2 : GO Annotation Protocol 3 : Wikipathways Annotation Protocol 4 : Links to diseases and possible side effects DisGeNET annotation Protocol 5 : Correlation of the phenotypic and bio-chemical screening data Protocol 6 : Compound tool box to validate/devalidate identified potential targets of protocol 1 based on IUPHAR database DiscoverX
20 OpenPhacts Provides the Required Semantic Integration DiscoverX
21 Pipeline Pilot Implementation of Protocol 5: Correlation Robot 1 Pull all Kinases from Tree 2 Pull Data for Phenotypic Assay 3 Pull Data for Each Kinase 4 Correlation Analysis 5 Output Table DiscoverX
22 Pipeline Pilot Implementation of Protocol 6: IUPHARDB 1 Read IUPHAR Interaction File 2 Get Uniprot IDs for Targets 5 Merged Output 3 Join Data 4 Distinguish Agonists/Antagonists DiscoverX
23 DiscoverX
24 Conclusion Biochemical broad profiling of existing proprietary kinase inhibitors allows to jump-start new projects and impact project decisions Janssen s approach the world is the laboratory allows to capitalize on our assets in a fast changing scientific environment The OpenPhacts platform delivered useful computational protocols for phenotypic screening data analysis DiscoverX
25 Acknowledgements Scott Bembenek Gary Tresadern Herman Van Vlijmen The Kinase Core and Extended Teams DSTT : Dario Alessi/Greg Findlay DiscoverX : Paul Gallant/Jeremy Hunt Eidogen : Steven Muskal OpenPhacts Team DiscoverX
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