The Kinase Knowledgebase

Transcription

1 The Kinase Knowledgebase Kevin P. Hambly Product Manager Derek A. Debe, Ph.D. Chief Scientific Officer

2 Outline About Eidogen-Sertanty Kinase Knowledgebase Overview Content Curation Process Data Structure & Organization Searching and Exporting Summary

3 About Eidogen-Sertanty Company Facts Formed in 2005 from merger of Eidogen & Sertanty Headquartered in San Diego, CA >$20M Invested in Technology Development Knowledge-Driven Drug Discovery Solutions Provider Offer informatics platform licenses: TIP TM and ARK TM Offer SAR Databases: Kinases & Custom Targets Offer DirectDesign TM Discovery Collaborations Variety of small, medium, and large customers

4 Example Customers KKB/ARK Target Informatics Platform Many more in 2006

5 Management Steve Muskal, Ph.D. Chief Executive Officer Derek Debe, Ph.D. Chief Scientific Officer Berkeley, MDL, Affymax/Glaxo, Libraria, Sertanty Caltech, Eidogen Joseph Danzer Senior VP, Product Development Caltech, Eidogen Scott Parker E. Coast Sales Manager Jerry Zaborowski W. Coast Sales Manager Chemical Abstracts (CAS), Tripos, Evotec, Sertanty Millipore, MSI, ABI, Rosetta Inpharmatics

6 Our Focus: Knowledge-Driven Discovery Eidogen-Sertanty has developed a unique, predictive informatics platform that leverages existing experimental data Leveraging earlier successes means higher success rates & reduced costs

7 DirectDesign: De- Know -vo Lead Design Available Chemicals Published Synthetic Strategies Proprietary Synthetic Strategies Target Family SAR Target Family Structures Ligand Binding Modes ChIP Library Generation Target Specific Libraries TIP & ARK Activity & Selectivity Assessment Compound Candidates Novel, Synthetically Accessible, Medicinally Relevant Compounds & Libraries Synthetic, Activity, and Structural Knowledge Leveraged Simultaneously

8 Kinase Knowledgebase (KKB) Kinase inhibitor structures and SAR data mined from >900 journal articles and >1100 patents KKB Content Summary (July 2005 Release): # of kinase targets: >200 # of SAR Data points: >160,000 # of unique kinase molecules with SAR data: >45,000 # of annotated assay protocols: >10,000 # of annotated chemical reactions: >2,300 # of unique kinase inhibitors: >390,000 (~340K enumerated from patent chemistries) KKB Growth Rate: Average 15,000 SAR data points added per quarter Average 25,000 unique structures added per quarter

9 Key Advantages 1) Customer Driven Prioritization Kinase target coverage directed by our customers Streamlined curation process enables rapid response to customer data requests 2) Experienced Curation Team Detailed curation process focused on high value information in kinase space Kinase family focus Have expertise to standardize and classify primary data 3) Flexible Data Access & Formatting Data readily mined through variety of sources (ARK, Daylight, MDL-Isis) Customizable exporting options 4) Integrated escreens Supplement real bio data with predicted activity Assess potential activity and selectivity before biological data is available Demonstrates utility of KKB data for QSAR model building 5) Broadened view of patent & scaffold space Enumerated products from common kinase synthetic schemes included in database 6) Continuous and accelerating quarterly growth rate >150 publications; >25,000 unique molecules; 15,000 SAR points added per quarter

10 Customer-Driven Hot Target Approach Kinase Targets of Clinical Interest from Vieth et al. Drug Discov Today. 10, 839 (2005). Eidogen-Sertanty Kinase Knowledgebase SAR Data point Distribution Primary targets w/ reported clinical data Reported secondary targets & targets w/ >60% ID

11 SAR Data Point Distribution (July 2005) >160,000 total SAR data points spanning >200 distinct kinase targets EGFR (14,406) VEGFR (9614) Tyrosine Kinases TK/TKL Groups PDGFR (5891) SRC FGFR TEC TIE2 ABL RAF Other TK & TKL Other non-kinase targets* Ser/Thr Kinases CK1/STE/CAMK/Other Groups IKK MAP2K AUR Other non-protein kinases Other protein kinases MAPKAPK Other AGC PKA PKC (13,077) Other CMGC MAPK (11,041) CDK (33,142) Ser/Thr Kinases CMGC Group Ser/Thr Kinases AGC Group *Non-kinase targets with activity data described in reference kinase literature are included in the KKB

12 Journal & Patent Coverage >1100 patents Years covered: : : : >750 U.S. (USPTO), European (EPO), & World (WIPO) >900 Journal articles Years covered: Journals represented Emphasis on comprehensive coverage for hot target IC50 data in J. Med. Chem., Bioorg. Med. Chem. Lett., & Bioorg. Med. Chem. KKB Growth Q2 04 to Q2 05 Patents & Articles Average >110 new patents, >30 new journal articles per quarter

13 SAR Coverage & Growth Rate >160,000 SAR Data points >105,000 from patents ~55,000 from journals >100,000 IC50 s >390,000 unique molecules >45,000 with at least one SAR data point ~345,000 reported without SAR data, or derived from enumeration using reported reactions & building blocks escreen predicted activities for ALL molecules KKB Growth Q2 04 to Q2 05 Data Points & Unique Molecules Average >25,000 new molecules, >15,000 new SAR points per quarter

14 Chemical Diversity and Drug Likeness * Diversity Analysis 45,684 Unique Molecules with Bio-Assay Data (as of July 2005) Drug-likeness Filtering Murcko-type Simplification Maximal Dissimilarity Clustering SMARTS-based Lipinski-based 14,226 unique fragments 4,234 chemotype clusters 43,080 passed (94.3%) 43,720 passed (95.7%) Well Represented Chemotypes 740 singletons Relevant, Drug-like Molecules

15 escreen QSAR Models 3D-QSAR models built from data annotated in KKB escreen Training Set Criteria (all data mined from KKB) Modes of ligand interaction with biological target? PKC: ATP site, phosphatidyl serine site, diacyl glycerol site, substrate site SRC: ATP site, substrate site, SH2-binding domain Substrate for the enzyme? Peptide, Carbohydrate, Pyruvate, ADP, Creatine What kind of assay was run? Ligands only grouped from purified enzyme assays What is the size and shape of the ligands in the assay protocol? Peptides, Small molecules, Heterocycles, unnatural amino acids, peptidomimetics Experimental assay conditions (ATP concentration 5-20 um) Is the information suspicious in the paper?

16 escreen Enrichment of Bio-Activity Space SAR-Based Activity Matrix

17 escreen Enrichment of Bio-Activity Space escreen Amplified Activity Matrix

18 escreen Example Prioritized 51,000 compound library using a collection of escreens Compounds screened in lung cancer cell-based assay* ~5-fold enrichment after screening 10% of the library. *Screening data courtesy of Hakim Djaballah, Memorial Sloan-Kettering Cancer Center 3,169 of the 51,000 compounds were active in at least one of 5 cell-based assays.

19 Content Curation Team Combine advantages of teams in India and US 9 Ph.D. and M.S. chemists and biologists SOP-guided, highly standardized and controlled work flow of data entry, quality control and final sign-off. Proprietary software mandates SOP s and archives all production details including data entry, quality control, and releases All data released from US and checked for data consistency Minimum Quarterly Updates (can be more frequent in ASP)

20 Quality Control Data Entry into DB Sub-database Data Quality Control Highly Standardized and Controlled Data QC workflow INDIA TEAM Sign-off Team Leader Quality/Consistency Check Quality and Content Feedback Use KKB data with confidence QC-controlled data sets Merge into Production DB (every 2 weeks) Production Database New data Final Data Check Grouping of SAR data points -Target - Assay protocol - binding site, etc. Assay Groups escreen model building U.S. TEAM

21 Content Prioritization New Customer Target Requests? Define Target Space Define Biological Search and/or Terms Chemical module Search journal and patent databases Patents: USPTO, EPO, WIPO Journals: PubMed, Infotrieve, ScienceDirect, ACS Comprehensive list of publications LEVEL 1 PRIORITIZATION (based on title, keywords, abstract, etc) Reduced list of relevant articles / patents LEVEL 2 PRIORITIZATION (based on type of biological data activity data) Enzyme Assay-IC50 Enzyme Assay-other Cell-based Assay Cell-free Assay Animal Models > > > > > ADME/PK data Rank relevant articles and patents to be captured

22 Prioritization Analysis: J. Med. Chem. Prioritization of J. Med. Chem. Citations (April 2005) Kinase Inhibitor Pubmed Search Level 1 Prioritization: Relevant Articles Level 2 Prioritization: Articles curated in KKB ~45% of kinase related J. Med. Chem. articles were curated for 2004.

23 Data Capture Primary data to be captured from journal / patent Biological Data Hierarchy Assay Type (e.g. Enzyme Assay, Cell-based Assay, Animal model) Assay Protocol (e.g. FGFR1 Kinase inhibition, CDK2/Cyclin E inhibition) Target (approved gene symbol) (e.g. CDK2, FGFR1, EGFR) O H O H H N N N N N H O O O N N N H Br H O O O H O O O N + H O N N N N H N H Molecular Structure Data Point Values (e.g. IC50 = 38nM, inhibition = 98.4 % at 100uM) Interconnected Data Model Easy navigation across the data hierarchy.

24 Big Pharma Deployment Example New KKB DATA (MDL/Direct compatible) Quarterly Updates Delivered by Eidogen-Sertanty ORACLE / MDL/Direct Multiple Interfaces, Multiple Types of Users ISIS/HOST ISIS/BASE Kinase Knowledgebase Direct Exports (SDF/ASCII) Data Pipelining In-house Application Development (Web-server) ARK Expert Users mining data directly Research Site 1 ~130 users Research Site 2 ~40 users Multi-Site Deployment, Simultaneous Data Access

25 Bio Assay Data Link to Bio Assay Data points and Protocols Example substructure search

26 Calculated Descriptors Link to Calculated Properties Example substructure search

27 escreen Results Link to escreen Results Example substructure search Predicted Active (escreen > 7.0) Predicted Active (escreen > 7.0)

28 Chemistry Protocols Link to Chemistry Articles, Reactions and Protocols Example substructure search

29 Chemistry Reactions Link to Chemistry Articles, Reactions and Protocols Example substructure search

30 Custom Exporting: Excel with ISIS Export SDF with custom fields Import Directly into ISIS for Excel

31 Searching: Multiple Substructure

32 Searching: Target Focused

33 Searching: Multiple Targets (Selectivity)

34 Searching: Multiple Targets (Dual Inhibition) Bio Activity + Predicted Activity

35 Kinase Knowledgebase Summary Highest quality kinase SAR database available, focused on data relevant for drug discovery and QSAR model building Experienced curation team and efficient processes leads to rapid and continuous database growth rate Enumeration from patented chemistry protocols allows broad view of patent space Flexible data model and licensing terms allows multiple simultaneous database access options