Slides for meeting to be held March 14th in Philadelphia - indications discovery and drug repurposing

1. In silico repositioning of approved drugs and collaboration for rare and neglected diseases Sean Ekins Collaborations in Chemistry, Fuquay Varina, NC. Collaborative Drug Discovery, Burlingame, CA. Department of Pharmacology, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ. School of Pharmacy, Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD.

2. Abigail Alliance for Better Access to Developmental Drugs Addi & Cassi Fund American Behcet's Disease Association Amschwand Sarcoma Cancer Foundation BDSRA (Batten Disease Support and Research Association) Beyond Batten Disease Foundation Blake’s Purpose Foundation Breakthrough Cancer Coalition Canadian PKU & Allied Disorders Center for Orphan Disease Research and Therapy, University of Pennsylvania Children’s Cardiomyopathy Foundation Cooley's Anemia Foundation Dani’s Foundation Drew’s Hope Research Foundation EveryLife Foundation for Rare Diseases GIST Cancer Awareness Foundation Hannah's Hope Fund Hope4Bridget Foundation Hypertrophic Cardiomyopathy Association - HCMA I Have IIH ISRMD (International Society for Mannosidosis and Related Diseases) Jacob’s Cure Jain Foundation Jonah's Just Begun-Foundation to Cure Sanfilippo Inc. Kids V Cancer Kurt+Peter Foundation LGMD2I Research Fund Lymphangiomatosis & Gorham's Disease Alliance MAGIC Foundation Manton Center for Orphan Disease Research MarbleRoad Mary Payton's Miracle Foundation Midwest Asian Health Association (MAHA) MPD Support National Gaucher Foundation National MPS Society National Organization Against Rare Cancers National PKU Alliance National Tay-Sachs & Allied Diseases Association New Hope Research Foundation NextGEN Policy Noah's Hope - Batten disease research fund Our Promise to Nicholas Foundation Oxalosis and Hyperoxaluria Foundation Partnership for Cures Periodic Paralysis Association RARE Project Ryan Foundation for MPS Children Sanfilippo Foundation for Children Sarcoma Foundation of America Solving Kids' Cancer Taylor's Tale: Fighting Batten Disease Team Sanfilippo Foundation The Alliance Against Alveolar Soft Part Sarcoma The Life Raft Group The NOMID Alliance The Transverse Myelitis Association The XLH Network, Inc. United Pompe Foundation Many of these groups are doing R&D on a shoestring how can we help? Just some of the many rare disease groups

3. Jonah has Sanfilippo Syndrome Jonah’s mum, Jill Wood started a foundation, raises money, awareness, funds ground breaking research happening globally. Willing to sell her house to fund research to save Jonah. She is in a race against time – what can we do to translate ideas from bench to patient faster? How do we get more ideas tested, who funds the research How can we help parents and families ? One example of why Pharmaceutical R&D needs disrupting

7. Ekins et al, Trends in Microbiology 19: 65-74, 2011 Fitting into the drug discovery process Insert your disease here…

8. Searching for TB molecular mimics; collaboration Lamichhane G, et al Mbio, 2: e00301-10, 2011 Modeling – CDD Biology – Johns Hopkins Chemistry – Texas A&M

13. Dataset Intersection Orphan + Common Use Orphan + Rare use In vitro hits 0 5 3 0 Do these represent frequent actives or promiscuous compounds?

14. Government Databases Should Come With a Health Warning Openness Can Bring Serious Quality Issues NPC Browser http://tripod.nih.gov/npc/ Database released and within days 100’s of errors found in structures Williams and Ekins, DDT, 16: 747-750 (2011) Science Translational Medicine 2011 This work was unfunded Science Translational Medicine 2011

15. Towards a Gold Standard: Regarding Quality in Public Domain Chemistry Databases and Approaches to Improving the Situation Antony J. Williams, Sean Ekins and Valery Tkachenko , Drug Discovery Today, In Press 2012 Data Errors in the NPC Browser: Analysis of Steroids Substructure # of Hits # of Correct Hits No stereochemistry Incomplete Stereochemistry Complete but incorrect stereochemistry Gonane 34 5 8 21 0 Gon-4-ene 55 12 3 33 7 Gon-1,4-diene 60 17 10 23 10

16. http://www.slideshare.net/ekinssean Ekins S and Williams AJ, MedChemComm, 1: 325-330, 2010. Need to learn from neglected disease research Do we really need to screen massive libraries of compounds as we have for TB and malaria? And groups are screening compounds already screened by others!

17. 2D Similarity search with “hit” from screening Export database and use for 3D searching with a pharmacophore or other model Suggest approved drugs for testing - may also indicate other uses if it is present in more than one database Suggest in silico hits for in vitro screening Key databases of structures and bioactivity data FDA drugs database Repurpose FDA drugs in silico Ekins S, Williams AJ, Krasowski MD and Freundlich JS, Drug Disc Today, 16: 298-310, 2011

20. PXR Antagonist Binding Site/s - Docking Ekins et al., Mol Pharmacol 72:592–603, (2007) 2 separate binding sites on either side of Lys277- identified with GOLD rigid docking in 1NRL chain A azoles would interfere with SRC-1 binding in the AF-2 site. One site is predominantly hydrophobic -15 amino acids. Lys277 most likely serves as a “charge clamp” for interaction between the co-activator SRC1 (His687) and PXR Azoles compete with SRC-1 for AF-2 Piperazine etc may not be necessary - Solvent exposed

22. PXR Antagonist Database Searching Finds New Hits SPB00574 2.14 24.8 SPB03255 2.22 6.3 Catalyst fit IC 50 (  M) Further similarity searching retrieved 4 active analogs of SPB03255 Also tested leflunomide – FDA approved drug 6.8  M Ekins et al., Mol Pharmacol, 74(3):662-72 , (2008)

24. Crowdsourcing Project “Off the Shelf R&D” All pharmas have assets on shelf that reached clinic “ Off the Shelf R&D” Get the crowd to help in repurposing / repositioning these assets How can software help? - Create communities to test - Provide informatics tools that are accessible to the crowd - enlarge user base - Data storage on cloud – integration with public data - Crowd becomes virtual pharma-CROs and the “customer” for enabling services

25. Massive models – using open tools Gupta RR, et al., Drug Metab Dispos, 38: 2083-2090, 2010 Can we get pharmas to share models rather than data – precompetitive? What can be developed with very large training and test sets? training 194,000 and testing 39,000 Open molecular descriptors / models vs commercial descriptors Potential to share models selectively with collaborators e.g. academics, rare & neglected disease researchers Lundbeck Pfizer Merck GSK Novartis Lilly BMS Allergan Bayer AZ Roche BI Merk KGaA

26. Future Drug Discovery Pharma R&D already looking like this – a big network I think we are seeing something like this with all the orphan disease networks too Massive collaboration networks – software enabled. We are in “Generation App” Crowdsourcing will have a role in R&D. Drug discovery possible by anyone with “app access” Ekins & Williams, Pharm Res, 27: 393-395, 2010.

28. Apps for collaboration ODDT – Open drug discovery teams Flipboard-like app for aggregating social media for diseases etc Create virtual drug discovery teams link to open notebook science Alex Clark, Molecular Materials Informatics, Inc Williams et al DDT 16:928-939, 2011 Clark et al submitted 2012 Ekins et al submitted 2012

30. The newest drug discovery reality Gone full circle Pharma now becoming more like rare disease groups Working on a shoestring, limited resources, leverages academics, partners with disease foundations, funded by them – open innovation Collaboration is a core element If Jill Wood or others can become a virtual pharma, if they have enough domain knowledge and drive Pfizer and other pharmas can be more like Jill, smaller, leaner, working on many more diseases as collaborators In silico approaches and collaboration = central to rare disease drug discovery