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High throughput screening (HTS) at iNovacia
- 1. iNovacia High-throughput Screening (HTS) Fragment Based Screening (FBS) Markus Thor Chief Business Officer right from the start markus.thor@inovacia.se www.inovacia.se iNovacia
- 2. iNovacia Laboratories Diversity Novelty Lead-likeness ~280,000 compounds Compound Collection Screening Structure- & Assay Based Target Lead Compounds Development Optimization LAB LAB High-Throughput Screening Medicinal Chemistry Fragment-Based Screening Crystallography Assay Development Mechanism of Action Studies Hit Validation Biophysical toolbox right from the start iNovacia
- 3. Assay Development &Screening LAB Diversity Novelty Lead-likeness ~280,000 compounds Compound Collection Screening Structure- & Assay Based Target Lead Compounds Development Optimization LAB LAB High-Throughput Screening Medicinal Chemistry Fragment-Based Screening Crystallography Assay Development Mechanism of Action Studies Hit Validation & Profiling Biophysical toolbox right from the start iNovacia
- 4. Assay Development &Screening LAB High-Throughput Screening • Successfully developed and used a large number of high-throughput screening assays • Successfull delivery of qualified chemical series in over 30 screening projects • Quality and speed in all steps e.g. use of acoustic dispensing to avoid artifacts Targets Format Examples of Technologies Nuclear receptors 384 FRET 384 Reporter Gene Assay Kinases 384 HTRF Proteases 384 FRET Metabolic enzymes 96-384 SPA, HTRF, Isotopic GPCRs 384 Ca-kinetics 384 cAMP, Isotopic Ion channels 384 Cellux: voltage/ion sens. probe right from the start Functional cell assays 96-384 Luminescence, fluorescence iNovacia
- 5. Assay Development &Screening LAB Compound Collection • ~280,000 cherry-picked compounds • High level of diversity (~100 compounds per scaffold) • Mix of exclusive, semi-exclusive and commercial Cherry- picked • Contains novel scaffolds Cherry- Biovitrum ~70,000 picked • Experimental ADME profiling Asinex and others ~200,000 • Chemical protocols available • QC by LC-MS validates integrity Exclusive, in iterative development ~10,000 right from the start iNovacia
- 6. Assay Development &Screening LAB Due Diligence Compound Collection Report from top-5 Pharma • 95 % of the compounds passed their stringent drug likeness criteria • 79 % where unique compared to their extensive compound collection • <1,5 % published with biological data • 35 % are not, or have not been, commercially available right from the start iNovacia
- 7. Assay Development &Screening LAB Fast and Flexible Sample Storage and Retrieval • Storage under N2, at +4 C, dark and dry. No measurable degradation since 2006. • Compound handling under inert atmosphere. • ~280,000 compounds in 1.4 ml microtubes • 10 mM dry DMSO stock solutions • All microtubes individually traceable • Fast cherry-picking • Ability to pick and plate during an HTS campaign to verify and validate. right from the start iNovacia
- 8. Assay Development &Screening LAB Filters introduced 2010 for Screening Set • The publication of new substructure filters for removal of Pan Assay Interference Compounds (PAINS) promted us to apply these filters and remove all PAINS from the iNovacia screening set. These compounds are not recognized by the filters commonly used to identify reactive compounds. (J. B. Baell and G. A. Holloway, J. Med. Chem., 2010, 53, 2719-2740.) • Redox active compounds identified by an in-house assay have been removed. Interestingly, we see a correlation between redox activity and PAINS. In a recent HTS, 79 hits were identified as being PAINS and 53 of those (67%) were also identified as redox active. • A few substructures that are not identified by the two filters above, but still appear as frequent hitters or suffer from lack of chemical stability have been removed. O O N S HN S N right from the start O N O H Examples of PAIN substructures iNovacia
- 9. Assay Development &Screening LAB Fragment-Based Screening • Scientists at iNovacia pioneers in developing fragment-based screening • Long experience and world-class competencies in NMR screening • Fragment libraries for primary screening – Primary screening by NMR: 900+ fragments containing 9-20 heavy atoms. Carefully designed with large numbers of readily available analogues from both commercial sources and the in-house iNovacia compound collection – Primary screening by biochemical assay at high compound concentration: 20,000 ”larger fragments” with MWs 200 - 350 right from the start iNovacia
- 10. Assay Development &Screening LAB Hit Validation & Profiling Identity/Purity/Stability/Solubility DRC and analysis HTS single Counter assays Clustering of confirmed hits point data Chemistry evaluation of hit series Tractability Library expansion Emerging SAR IP space Biophysical assays Dynamic Light Scattering (DLS) Nuclear Magnetic Resonance (NMR) Microcalorimetry (DSC/ITC) Final prioritization Surface Plasmon Resonance (SPR) of hit series Mass spectrometry (ESI-MS/MALDI-MS) Full chemistry Analogs In-house, commercialy available, small program expansions by parallel chemistry, SAR analysis In vitro ADME assays HSA binding, CYP inhibition, membrane affinity, metabolic stability, hERG binding, right from the start cytotoxicity iNovacia
- 11. iNovacia Laboratories Diversity Novelty Lead-likeness ~280,000 compounds Compound Collection Screening Structure- & Assay Based Target Lead Compounds Development Optimization LAB LAB High-Throughput Screening Medicinal Chemistry Fragment-Based Screening Crystallography Assay Development Mechanism of Action Studies Hit Validation Biophysical toolbox right from the start iNovacia
- 12. Structure-Based Optimization LAB Validated Hits to Competitive Lead Series • Efficient chemical expansion and increasing the odds – Through early SAR generation (in-house analogs, parallel chemistry and/or x-ray crystallography) – Through high quality chemical starting points – Through high quality pharmacological profiling • Highly integrated work flow – Medicinal chemistry – Pharmacology – Crystallography (in collaboration with Sprint Biosciences) – ADME – Automatic data capture and ELN right from the start – Humanized ex vivo and in vivo models within cancer iNovacia
- 13. Typical Project Scopes Customer Characteristics Typical Service Segment Smaller Biotechs Typically strong in specific disease General step-wise support in drug area biology. discovery ranging from assay development to lead optimization Seek access to drug discovery expertise and technology Larger Biotechs Fully integrated research in-house Full projects ranging from assay and Often lack HTS/FBS capacity development to lead series generation. Mid-sized Pharmas Seek access to additional screening technologies, novel lead series Big Pharmas Fully integrated research in-house Full projects ranging from assay development to lead series generation. Seek chemical diversity/novel lead series, additional capacity, complementing approaches and fresh thinking right from the start iNovacia
- 14. Key Success Factors The Right PEOPLE The Right ATTITUDE Excellence in OPERATiONS Vast Pharma EXPERiENCE right from the start iNovacia
- 15. The History ofiNovacia 1996 Merger of Pharmacia & Upjohn Small molecule Center of Excellence formed in Stockholm 2001 Biovitrum spins out from Pharmacia Corporation Biovitrum small molecule deals Continued investments in small molecule R&D 2002 - 5HT2c deal with GSK 2003 - 11beta HSD deal with Amgen 2006 Management buy-out of iNovacia Asinex Ltd invests in iNovacia 2007 iNovacia: First Big Pharma deal 2008 iNovacia: First deal in the US 2010 2011 Karolinska professors and iNovacia Kancera acquires iNovacia and management establish Kancera AB is listed on the Nasdaq OMX First North right from the start iNovacia