DuPont Pharmaceuticals Company Utilization of Spotfire™ in Quality Assessment & Analysis of Screening Data Thomas D.Y. Chung, Ph.D. Sr. Director, Leads.

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Presentation transcript:

DuPont Pharmaceuticals Company Utilization of Spotfire™ in Quality Assessment & Analysis of Screening Data Thomas D.Y. Chung, Ph.D. Sr. Director, Leads Discovery Operations Dupont Pharmaceuticals Company Wilmington, DE © 2001, DuPont, Inc. - All Rights Reserved.

DuPont Pharmaceuticals Company Target Number of Screens (Attrition Model) NDA Pre- IND Med CHEM Early CHEM Qualified LEAD New HTS No. of Cmpds K Decision Cost & Quality $$$$$

DuPont Pharmaceuticals Company Spotfire Utilization in DuPont Pharma Leads Discovery Data QC review and artifact alerts Survey screen performance & consistency Decision support for compound selectivity assessment Allows easy selection, justification, and communication of desired “hits” Summary views on multivariate data for HT- ADME and Pharmaceuticals Properties Profiling

DuPont Pharmaceuticals Company Compound Progression Schema 1º HTS w/ or w/o Counterscreen (singlet or replicate) Plate & Run QC/ Post run filtering Confirmations of solutions & Dose Response Curves (DRC) Review of stats, false positives & negatives, & self-consistency of %I or %A and IC50 or EC50 Check chemical structure for obvious flaws HIT SELECTION, CONFIRMATION & DOSE-RESPONSE Obtain independent sample (check lots), powder if available. Confirm purity, identity & bioactivity of major peaks. LC/MS Refine dose-response curve SAMPLE POTENCY & IDENTITY CONFIRMATION Look for nascent SAR - similarity & substructure Selectivity & P3 profiles & liabilities Chemical attractiveness & starting point for optimization Bioassay in TA in vitro & in vivo models NEW LEAD SERIES? LEAD SAR, QUALIFICATION & PRIORITIZATION I. CONFIRMED HIT Is solution activity confirmed, potent (selective?) & chemically interesting? II. CONFIRMED ACTIVE Is independent sample (solid or liquid) potent, pure & structure correct? III. QUALIFIED LEAD SERIES Is structure “druggable”? Acceptable selectivity, P3 properties, chemical tractability, TA bioeffect

DuPont Pharmaceuticals Company Liquid Handling Validation

DuPont Pharmaceuticals Company Assay Run QC - Spotfire Pro  Stack view Good run Stack view Severe Edge Effects

DuPont Pharmaceuticals Company Assay Confirmation QC- Spotfire™.net

DuPont Pharmaceuticals Company Run QC - Plate Drill-down Spotfire™.net

DuPont Pharmaceuticals Company Selectivity Profiling

DuPont Pharmaceuticals Company Compound Number Analytical Quality Low Medium Very High HTS Specificity/Chem Analysis Solub/SPB/ Bioavail /Metab HTS to SAR SAR Solub/SPB/Bioavail/Metab Primary Screen Lead Qualification Progression v

DuPont Pharmaceuticals Company Desireable Drug-Like Characteristics Pharmacologically active and specific Favorable oral bioavailability soluble membrane permeable reasonable uptake not substrate of efflux-pumps Desirable pharmacokinetic properties distribution and clearance 60%-90% serum protein binding metabolism low toxicity no drug-drug interactions not substrates for cytochromes P450

DuPont Pharmaceuticals Company HT- Pharmaceutical Properties Profiling Purity & Bioactivity Correlation CYP 3A4, 2D6 & 2C9 Inhibition Pgp Efflux Inhibition Serum Binding Solubility* - nephelometry or UV/LC Metabolism* - liver microsomes/cells Permeability - surface activity (tension)

DuPont Pharmaceuticals Company Acknowledgments Ilona Kariv Louis Coudurier Gerard McGeehan