Benefits of Contracting CDTResearch Partnership from Target ID through IND and beyond Problem Solvers – Experienced drug discovery team – Broad Technology Base Mechanistic enzymology – industry leading Biochemical and cell biology assay development Biomarker assay development Computational and Medicinal Chemistry Partners – Communication – Versatile and flexible – Project leadership/consultation – partner in strategy and execution
Computational & Medicinal Chemistry Experience where it counts: Ala 51 – Drug Design Thr 106 – Synthetic Route Analysis Lys 53 – Compound Synthesis Met 109 Glu 71 – Structure-Based Drug Design – Molecular Modeling Leu 167 – Virtual Screening Asp 168 Confluence can enable at all stages: Asp 112 Ser 154 – Understanding the Competitor Landscape – Discovering Areas with Freedom To Operate – ID Leads from Virtual Screen – Parachute Opportunity Exploitation – Designing Initial Chemical Matter – Identifying Synthetic Routes – Providing Active Pharmaceutical Ingredients – Writing Patent Protocols – Optimizing Current Lead Matter – Singleton and Library Production
Assay Establishment and ValidationWe can deliver a validated assay where no off the shelf option exists Assay Development Expertise – Flexible screening formats – Biochemical and Cellular assays – Direct HTS translation Appropriately Equipped – 96 and 384 well enabled – Multiple liquid handling stations – Versatile plate readers Data Analysis and Secondary Assays – Hit validation and IC50 values – Mechanistic characterization of hits – Follow-up orthogonal assays Problem Solving – New targets – need entire testing funnel – Complex signaling systems – Challenging targets – Exclusion of artifacts Medium Throughput Specialty Screens
Biochemistry/Enzymology Mechanism of Action Studies Enzyme Activity Direct Binding Thermodynamics Radioligand Biacore Isothermal Titration Steady State Kinetics TR-FRET Calorimetry Fluorescence (FP) Absorbance Luminescence Inhibitory Mechanism Filtration Competitive Noncompetitive Independent of Catalysis Uncompetitive Kd and stoichiometry Irreversible (kinact & Ki) Independent of Catalysis DH, DS, DG Slow tight binding (kon & koff) Binding kinetics (kon & koff) Aggregate (non drugable) Key to Increased Efficiency of Lead Discovery & Development is to Link SAR to Mechanism of Action!
Cell-Based Assay Design & Development Cell-based assays are invaluable for drug discovery: Intracellular and Secreted Analyte Analysis – Identification of biologically important signal transduction 120 120 pathways and key point(s) for therapeutic intervention Protein Activity 100 100 % of Stimulated Control) % of Stimulated Control) Intracellular Analyte – Understanding compound mechanism of action Secteted analyte, 80 80 – Quantitation of efficacy and selectivity 60 60 – Understanding safety issues linked to pathways 40 40 Cell-based assays have inherent problems in: 20 20 – Simulating ex vivo the microenvironment/disease state/species and/or tissue 0 - Stim 0mM 0.01mM 0.1mM 1.0mM 10mM 0 [Inhibitor] – Choosing disease relevant cell types and/or stimuli +Stimulation – Genetic drift, inter-donor variability, cross-species, etc. – Understanding effects of enzyme isoforms, scaffolding, Cellular Quantitation of Kinase Inhibitor Selectivity substrate selectivity, etc. Kinase 1 200 Kinase 2 Confluence scientists have experience with these issues: Phospho/Total (% Control) Kinase 3 150 – We can identify & design validated assays for translatable target modulation & efficacy biomarkers 100 – Offer broad assay technologies including DELFIA/FRET, AlphaScreen, Westerns, FACS etc. 50 – Biomarkers selected for assay development based on pertinent scientific literature and our collective experience 0Coupling Assay Technology with Biological Relevance Kinase Inhibitor (nM)
Biomarker Development Reliable interpretation of preclinical disease and pharmacology models and human clinical studies requires suitable biomarker analysis to optimally relate PK/PD, PK/TD and outcomes. CDT is Experienced With: 100 – Target, Mechanism and Disease Biomarkers 90 Target Mechanism % Control Response 80 – Biomarker selection Disease 70 – Biomarker assay design, development, 60 validation and interpretation 50 – Cell surface, intracellular and secreted analytes 40 30 CDT Can Deliver: 20 – Assays developed across species and in 10 various biological matrices 0.1 1 10 100 – Complete statistical evaluation of data Dose (mg/kg) – Seamless assay transfer to the clinical CRO We can help you generate an interpretable and decision-enabling cellular, animal or human study though effective use of translatable biomarkers.
Confluence TeamManagement: Staff Scientists: Joseph Monahan, PhD, President Barry Burnette, PhD Michael Kuo, MD, Board Member Jeff Hirsch, BS Al Beardsley, PhD, Business Development Balekudru Devadas, PhD Walter Smith, MS, Vice President Research Susan Hockerman, MSScientist Founders: John Springer, MS Gabriel Mbalaviele, PhD Jerry Cubbage, PhD Shaun Selness, PhD Jim Blinn, MS Heidi Hope, PhDBusiness Professionals: Arthur Wittwer, PhD Jennifer Bohnert – Controller William Hood, MS Lisa Gabel - Bookkeeper Sheri Bonar, BA Polsinelli Shughart - General Counsel Matt Saabye, BS Harness, Dickey & Pierce - IP Attorney Jon Jacobsen, PhD Stone Carlie - Tax Advisor Taryn Syrtees, BS Kristin Sauer, BS
Joseph Monahan, PhD Walter SmithPresident Vice President ResearchConfluence Discovery Technologies Confluence Discovery TechnologiesCORTEX Bioscience District CORTEX Bioscience District4320 Forest Park Avenue, Suite 303 4320 Forest Park Avenue, Suite 303St. Louis MO 63108 St. Louis MO firstname.lastname@example.org email@example.com www.confluencediscovery.com314.932-4032 x-305 314.932-4032 x-305