2. Benefits of Contracting CDT
Research 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
3. 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
4. Assay Establishment and Validation
We 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
5. 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!
6. 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 0
Coupling Assay Technology with Biological Relevance Kinase Inhibitor (nM)
7. 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.
10. Confluence Team
Management:
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, MS
Scientist Founders: John Springer, MS
Gabriel Mbalaviele, PhD Jerry Cubbage, PhD
Shaun Selness, PhD Jim Blinn, MS
Heidi Hope, PhD
Business 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
11. Joseph Monahan, PhD Walter Smith
President Vice President Research
Confluence Discovery Technologies Confluence Discovery Technologies
CORTEX Bioscience District CORTEX Bioscience District
4320 Forest Park Avenue, Suite 303 4320 Forest Park Avenue, Suite 303
St. Louis MO 63108 St. Louis MO 63108
josephmonahan@confluencelifesciences.com waltersmith@confluencelifesciences.com
www.confluencediscovery.com www.confluencediscovery.com
314.932-4032 x-305 314.932-4032 x-305