Mel Reichman, senior investigator and director of the LIMR Chemical Genomics Center at the Lankenau Institute for Medical Research presents at the chemistry department at Drexel University on November 12, 2009. Modern drug discovery by high-throughput screening (HTS) begins with testing hundreds of thousands of compounds in biological assays. The confirmed hit rate for typical HTS is less than 0.5%; therefore, 99.5% of the costs of HTS are for generating null data. Orthogonal convolution of compound libraries (OCL) is 500% more efficient than present HTS practice. The OCL method combines 10 compounds per well. An advantage of this method is that each compound is represented twice in two separately arrayed pools. The potential for the approach to better enable academic centers of excellence to validate medicinally relevant biological targets is discussed.

1. Accelerating Exploration of Chemical and Biological Space for Academic Drug Discovery [email_address] . www.limr.org (see research Services—LCGC)

2. Lankenau Institute for Medical Research (LIMR). Wynnewood, PA is an non-profit organization of ~22 independent faculty and other principal investigators who conduct basic and clinical research in cancer, diabetes, and cardiovascular disease. Founded in 1927. “ In medicine, hope springs from research”

4. American Academia: A Golden Goose of Innovation? $100 Billion $500 Billion Bayh-Dole Act 1980

5. Strangling a Golden Goose The COX-2 Story

6. Greasy Aryl Polar Celebrex Greasy Aryl Alkyl Acidic Ibuprofen

7. The COX-2 Story: Timeline 1992: Patent filed 1992: Merck and Searle begin COX-2 program 1998: Celebrex approved, 6 months later Vioxx approved 4/11/2000: U.S. Patent No. 6,048,850 (the '850 patent) issues (‘kitchen sink’) 4/12/2000: UR initiates suit against Searle (Pfizer) 3/5/2003: UR looses up to Supreme Court October, 2003: NIH Roadmap announced

8. Why UR Lost “ Because the inventors here simply failed to take the last critical step of actually isolating a compound, or even developing a process through which one of skill would be directly led to such a compound, this patent involves "little more than a research plan," the court concluded. ( http://pub.bna.com/ptcj/006161.pdf ). ‘ The University had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and, therefore, the patent was invalid.’

9. "We are the National Institutes of Health, not the National Institutes of Biology," Elias A. Zerhouni, M.D. says. "We need to reengineer how we apply our research to humans." ( http://www.the-scientist.com/2004/2/16/44/1 ) New Roadmap for 21 st Century Translational Research

10. Harbinger of Change

12. Proboscis for Probes? volume 5 number 7 JUly 2009 nature chemical biology

13. http://genome.gov/Pages/About/OD/ReportsPublications/AustinHHT060806.pdf With New Models In place

16. Important Product Usage and Safety Information The ABBOTT PRISM HIV O Plus test (Human Immunodeficiency Virus Types 1 and 2 (E. coli, B. megaterium, Recombinant) Antigen and Synthetic Peptide) can be used by laboratory professionals to screen individual donations of blood for antibodies to HIV-1 (anti-HIV-1) Groups M and O and /or antibodies to HIV-2 (anti-HIV-2). ABBOTT PRISM HIV O Plus can also be used as an aid in the diagnosis of HIV-1/HIV-2 infection. This assay has not been validated for use with pooled specimens and is not intended for use on cord blood specimens.

18. MX 1-10 epsilon delta gamma beta alpha

19. New Approaches, Software and Data Mining www. ceuticalsoft .com

20. The retinoblastoma tumor suppressor pathway contains multiple oncogenes (green) and tumor suppressors (red) and is dysfunctional in almost every human tumor Münger K PNAS 2003;100:2165-2167

22. Pilot Run Library OCL009 9 E7-inhibitors—pRB/E2F

23. Trends Observed for Hit Categories E7/pRB-E2F    Conf. Rate

24. Fructosamine –3-Kinase Pathway in Diabetes Fructoselysine Glucose + Lysine Fructoselysine-3- Phosphate FRUCTOSAMINE- 3- KINASE 3DG + LYSINE + Pi Glycated Protein DIET DIABETICS Fructoselysine Glucose + Lysine Fructoselysine-3- Phosphate 3DG + LYSINE + Pi Glycated Protein NON-DIABETICS Diabetic complications Nephropathy Retinopathy Neuropathy Kindly provided by Dynamis Therapeutics Inc.

25. ADP

26. Universal Kinase Assay

27. Pilot Run Library OCL009 9 FN3K Inhibitor Screen

28. Pilot HTS Results Library LCGC-OCL-009 HTS Results 8 x 8,000 compounds = 64K

29. Advanced, Innovative Compound Management Strategies

32. Indelible Audit Trail -20 o C Operation Consolidate Molecular Diversity Collections Maxiprep genomic DNA extractions for molecular epidemiology studies and biorepositories. CA Garcia-Sepulveda et al., Mol Biol Rep. 2009 Jul 17 Toward noninvasive genomic screening of lung cancer patients. L V Sequist et al., Journal of Clinical Oncology, Vol 27, No 16 (June 1), 2009 epsilon delta gamma beta alpha Abbreviated HTS

33. FIGURE 3

34. Present Biorepository Practice