Dennis Wright, Ph.D. Professor of Medicinal Chemistry NPDD Initiative UCONN School of Pharmacy University of Connecticut

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1 Craig M. Crews, Ph.D. Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology Chemistry, Pharmacology Center for Molecular Discovery Yale University Dennis Wright, Ph.D. Professor of Medicinal Chemistry NPDD Initiative UCONN School of Pharmacy University of Connecticut

2 PITCH: What?

3 PITCH: What? An Collaboration between Yale and UCONN to Help Academic Projects Cross the Valley of Death

4 PITCH: What? Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics

5 PITCH: What? Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics Increase the number of biotech companies in the State by encouraging faculty entrepreneurism

6 PITCH: What? Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics Increase the number of biotech companies in the State by encouraging faculty entrepreneurism Employ the latent pool of pharmaceutical talent statewide

7 PITCH: What? Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics Increase the number of biotech companies in the State by encouraging faculty entrepreneurism Employ the latent pool of pharmaceutical talent statewide Establish a new paradigm for robust, synergistic research programs between Yale and UCONN, and ultimately to other institutions in the state

8 PITCH: What? Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics Increase the number of biotech companies in the State by encouraging faculty entrepreneurism Employ the latent pool of pharmaceutical talent statewide Establish a new paradigm for robust, synergistic research programs between Yale and UCONN, and ultimately to other institutions in the state Recruit additional venture investment to the state

9 PITCH: What? Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics Increase the number of biotech companies in the State by encouraging faculty entrepreneurism Employ the latent pool of pharmaceutical talent statewide Establish a new paradigm for robust, synergistic research programs between Yale and UCONN, and ultimately to other institutions in the state Recruit additional venture investment to the state Put Connecticut on the map for a new paradigm in drug discovery

10 PITCH: Who? Craig M. Crews, Ph.D. Lewis B. Cullman Professor of Molecular, Cellular, and Dev. Biol. Chemistry, Pharmacology Center for Molecular Discovery Yale University Dennis Wright, Ph.D. Professor of Medicinal Chemistry NPDD Initiative UCONN School of Pharmacy University of Connecticut

11 PITCH: Who? Background West Liberty State BS (Chemistry) Ohio University Ph.D. (Chemistry) Stanford Postdoc Training UCONN Joined Faculty in 2006 Experience New Pathways in Drug Discovery (NPDD) -Co-Founder Dennis Wright, Ph.D. Professor of Medicinal Chemistry NPDD Initiative UCONN School of Pharmacy University of Connecticut Promiliad, Inc. -Co-Founder Synaptic Dynamics, Inc. -Co-Founder

12 PITCH: Who? Background U.Va. BA (Chemistry) Harvard Ph.D. (Biochemistry) Harvard Postdoc Training Yale Joined Faculty in 1995 Experience Yale Center for Molecular Discovery (YCMD) -Founder/Executive Director Craig M. Crews, Ph.D. Lewis B. Cullman Professor of Molecular, Cellular, and Dev. Biol. Chemistry, Pharmacology Center for Molecular Discovery Yale University Proteolix, Inc. -Co-Founder Arvinas, Inc. -Founder -Chief Scientific Officer

13 PITCH: Where? Yale Center for Molecular Discovery (YCMD) Yale West Campus (former Bayer Pharmaceuticals)

14 PITCH: Where? Established in 2003 Occupies building B27 with ~10,000 sf of laboratory and office space 9.5 staff: 7 Ph.D., 2 M.S., 1.5 B.S. 332 Projects in past 5 years with investigators from 25 Yale departments Craig M. Crews, Ph.D. MCDB/Chemistry/Pharmacology Numerous prominent publications Providing target identification, small molecule sirna screening, and medicinal chemistry services Multiple corporate interactions and start-ups Janie Merkel, Ph.D. Director of Biology Denton Hoyer, Ph.D. Director of Chemistry

15 PITCH: Where? 9.5 Full Time Employees 5 Biology 3 Chemistry 1.5 Administrative Experience in Academia & Industry:

16 PITCH: Where? Overview of Capabilities Biology Assay Development High Content Imaging Screening (sirna and small molecule) Chemistry Structure-Activity Modeling Medicinal Chemistry Compound Synthesis & Analoging Assisting with Patent Writing 16

17 PITCH: Where? Liquid Handling & Robotics 96-, 384-, 1536-well plate compatibility Sterile or Non-Sterile Environments YCMD Resources Multiple Types of Readouts At molecule level: Protein-protein, Enzymatic assays Cell-based, Organism-based assays High Content Screening - Highly subsidized costs Medicinal, Computational & Synthetic Chemistry Synthetic planning & execution/outsourcing Structure and Ligand-based drug design Optimization of ligand potency and pharmacokinetics Experience with Multiple Therapeutic Areas Oncology, Neurodegenerative, Infectious Diseases, Inflammation, Cardiovascular

18 PITCH: Where? Assay for Inhibitors of NPP4 Activity R. A. Albright et al Blood, (2012) 120: Novel Composition of Matter Proof of Concept (Repurposing) X-Ray Structure of Target Classical High Throughput Screening Follow-On Improvement Structure-Based Design Demetrios Braddock, Department of Pathology

19 PITCH: Where? UCONN Storrs The NPDD is a cross-college initiative dedicated to drug discovery and development with faculty from Pharmaceutical Sciences, Chemistry, MCB and UCH/CICATS New Pathways to Drug Discovery UCONN Health External Partners NPDD: A Drug Discovery Network

20 UCONN School of Pharmacy The SOP provides an exciting, highly interactive environment for experimental therapeutics with scientists from a broad range of backgrounds united by an interest in drug discovery and development. We are organized into three disciplines Medicinal Chemistry: expertise in drug design, drug target structure and mechanism of action Pharmacology/Toxicology: expertise in liver toxicology, metabolism and stem cell biology Pharmaceutics: expertise in small molecule formulation, formulation of biologics and drug delivery

21 Medicinal Chemistry Capabilities Medicinal Chemistry Structure-Based Drug Design High-Throughput Screening Drug design/sar X-ray crystallography Complex Biomolecular NMR molecule/parallel Docking synthesis Virtual Screening Stereoselective Rational Design synthesis In vitro metabolism Physico-chemical property determination Automated handling 150K lead library Pharmacological Screens (LOPAC) Target and Phenotypic screens

22 Drug Target Studies at UCONN Health Protein Expression Protein Purification Protein Characterization High Field NMR (800 MHz) Other Biophysical Studies

23 PITCH: How? UCONN Yale External Advisory Board Evaluation Assay Submission Due: October 1

24 PITCH: How? UCONN Yale Bill LaRochelle, (Sr.Dir, Roche Sequencing Solutions Brian Dixon, (CEO, BioRelix) Peter Farina, (SVP, Boehringer Ingelheim) Amy Burd, (Exe. Dir. Res Strategy, Leukemia & Lymphoma Society) Henry Showell (Sr. Res Fellow, Pfizer) External Advisory Board Evaluation Assay Submission Live Presentations to the EAB 10am-1:30pm October 30 Yale Center for Molecular Discovery (YCMD) West Haven, CT

25 PITCH: How? UCONN Yale External Advisory Board Evaluation Assay Submission Assay Development Assays Screened Virtual Hit Expansion SAR/ Med Chem [in vivo Testing] Business Plan Pitch YCMD UCONN Protein Production Core YCMD UCONN Pharm Originating Lab or CRO New Leaf Ventures Elm Street Ventures OrbiMed Ventures Canaan Partners Ventures Other VCs/Pharma Venture Funds? Out-license?

26 Three Year Goals # Assays Submitted? 36 Assays Developed 30 Assays Screened 24 Virtual Hit Expansions 12 SAR/ Med Chem 8 Business Plans 8 Pitches

27 PITCH: When? Deadlines: Submission of Slidedeck PITCH Application: October 1

28 PITCH: When? Deadlines: Submission of Slidedeck PITCH Application: October 1 Faculty Presentation to External Advisory Board: October 30 th (at the YCMD)

29 PITCH: When? Deadlines: Submission of Slidedeck PITCH Application: October 1 Faculty Presentation to External Advisory Board: October 30 th (at the YCMD) Notification of Awards: Mid November

30 Project Title Investigators 30 To see TIPS and FAQS for each slide, please look at this template in Notes view.

31 Two Year Goal Statement Your two year goal will frame the following assessment. 31

32 Project Team Brief background for team members and their roles on this project. Include relevant past experience, if any. Identify unfilled roles needed. 32

33 Scientific Background and Opportunity Briefly, introduce background science. What is the problem worth solving? What is your solution? Why is it novel? 33

34 Research Plan Describe additional research data needed but which is outside the scope and capability of the investigator s laboratory. 34

35 Assay Feasibility Assessment 1. Describe your target and biological pathway 2. Does biochemical assay exist? 3. Does a cell-based readout exist? 4. What are assay readouts for all assays (e.g. luminescence, fluorescence intensity, image-based, others)? 5. What is your level of experience with the assays? 6. Are all critical reagents for the assays currently available? 35

36 Med. Chem. Feasibility Assessment 1. Target location(s): extracellular, intracellular, CNS, etc. and tissue type. 2. Can the protein be reliably expressed and purified? How? 3. Does crystal structure of target exist, resolution and RCSB code. If no, what are the closest homologs with crystal structure coordinates? 4. Predicted binding pocket affinity of target (YCMD determined); i.e., is the target druggable? 5. Are small molecule inhibitors known? 6. Synthetic accessibility (conducted after HTS analysis) 36

37 Clinical Correlation Assessment 1. Is the biology (i.e. pathway) well characterized? 2. Has modulation of the pathway been shown to correlate with changes in disease burden (e.g. phenotype of KO mice, relevant animal studies, GWAS) 3. Is there precedent for the MOA for similar disease targets? 4. Is there a reliable and predictive animal model that has a history in translating compounds to the clinic? 5. Does a clinically relevant biomarker exist? 6. Competition: Examine approved claims (efficacy and safety) of competitors. Examine the competitive environment for compounds currently in 37 development.

38 Clinical Need/Potential Market 1-2 slides addressing Scope of unmet medical need Number people affected by disease (target population) Current standard of care and market size (commercial potential) Unique needs of the target population Phase II proof of mechanism and patient stratification strategy 38

39 Targeted Product Attributes 1 slide describing the desired characteristics of the proposed therapeutic for the intended indication What is the specific value of your drug/approach to patients? What advantages does it offer over existing or competing approaches? How your product meets the needs of your global market based upon performance features, costs, robustness, etc. 39

40 Intellectual Property Position 1 slide addressing OCR/T2 disclosure and patentability status 40

41 Questions about the Program? Contact Craig Crews (Yale) or Dennis Wright (UCONN) Craig Crews (203) Dennis Wright (860)

42 Questions about the Application? Contact Janie Merkel (YCMD) (203)

43 Thank You