TimTec History Highlights

2. TimTec History Highlights • 1995: TimTec Corporation was established in USA, Delaware as a distributor of Zelinsky Institute (Moscow, Russia) and also began providing compounds weighing and handling services • 1996-97: TimTec expands compound sources to numerous research centers around the world • 1998-2004: Cheminformatics technology development, database management, broadened supplier sources; became one-stop shopping vendor for screening compounds; partnership with Sigma-Aldrich (LOPAC), BioMol (MaxiVerse), Nacalai Tesque. • 2005-2007: 10-year anniversary. New products: ApexScreen, Natural Products and MyriaScreen (Sigma-Aldrich). Collaboration with EnBioTec, Japan, screening, lead discovery project.

3. TimTec • Headquarters in Newark, Delaware, USA • Operations • Database management • Marketing and business development • Supplier network management • Computational services • Compound management and storage facilities • Liquid handling, labeling and bar-coding services • Currently expanding facility, personnel and instrumentation to fulfill needs of growth

4. TimTec Key Contacts • Dr. Murat Niyazymbetov - President and CEOB.S., Mendeleev University, Ph. D., Zelinsky Institute. Worked at Zelinsky Institute of Organic Chemistry, University of Delaware, Electrosynthesis Company; more than 70 scientific publications. • Ms. Kay Denisova - Marketing and Bus. Dev., TimTec Products and Services Consulting. Kay@timtec.net, 1 302 292 8500 x 202 • Dr. Robert J. Chorvat - Medicinal Chemistry Business Development, Consulting. 15 Years DuPont Pharmaceuticals; 18 Years Searle/Pharmacia; 40 publications, 36 US patents. • Mr. Tim Niazoff - Director, Information Technology, Software Products and Computational Services Consulting.Tim@timtec.net, 1 302 292 8500 x 203 • Mr. Olga Niazoff – VP Finance and Accounting. Olga@timtec.net, 1 302 292 8500 x 204

5. TimTec Products • Compound libraries • General screening • Targeted • Diversity • Template-based • Privileged structure • Custom Libraries • Individual compounds • Natural Products • Pure individual compounds • Plant extracts • Semi-natural and Derivatives • Building blocks and intermediates

6. TimTec Database Accessibility TimTec Database Over 5 Million compounds ACD Database and others Commercial Vendors Non-exclusive chemists throughout Europe/Asia TimTec-exclusive Chemists throughout Europe/Asia

7. Compounds characteristics • Individually synthesized • Purity - at least 90%, average 95% • NMR (300 MHz or higher) and MS • Possess drug-like properties • Molecular Weight 160 - 600 • No reactive groups • No heavy metals • Available in vials and/or 96/384-well plates

8. Lipinski Rule of Five Distribution • Molecular mass not greater than 500 • LogP not greater than 5 • No more than 5 hydrogen bond donors • No more than 10 hydrogen bond acceptors

9. Molecular Weight Distribution

10. Libraries Overview TimTec libraries are characterized according to the following features that may overlap from collection to collection: • General screening collections, which would include specifically drug-like and generally diverse selections • Targeted, specialty compound collections, ActiTarg Series, template based, etc. • Nature Inspired: pure natural material or natural product derivatives and plant extracts • Different size: There are collections of 5,000cmpds, 10,000cmpds, 25,000cmpds, 50,000cmpd, or even 75-100,000cmpds. The latter would be grand ActiMol collection, our primary stock • Custom: collections selected based on suggested criteria • Formatting options: compounds in dry form or in solutions

11. Diversity Libraries • A selection of compounds from currently available stock that represents the greatest chemical diversity for a specific number of compounds from that library • Proprietary software is used for these selections • Available Diversity Libraries: • ActiGlobe 50K • ActiProbe 25K, 10K • ApexScreen 5040 • RareCSC (under dev.) • MyriaScreen (Sigma-Aldrich) • MaxiVerse (BIOMOL)

12. ActiGlobe-50K The grand diversity collection of 50,000 compounds has been assembled from world wide sources numbering over 2,000,000 compounds-candidates. The collection has molecules representing the chemical diversity of screening samples produced by labs and research centers throughout the world. In addition to adherence to Lipinski parameters, dozens of advanced filters have eliminated undesirable atoms, functionality and fragments creating a library that will provide exceptionally good chemical starting points for hit and ADMET optimization. Due to large file size, ActiGlobe-50K database is available on request for online download. Please call 1 302 292 8500 x 203 or e-mail at tim@timtec.net

13. ActiProbe-10K and 25K • Screening sets of 10,000 and 25,000 compounds respectively originated from ActiGlobe-50K library. Both collections were selected through Jarvis-Patrick clustering. The overlap between ActiProbe-10K and ActiProbe-25K is about 4,500 compounds. Jarvis-Patrick clustering permits sampling of large library pools through selection of molecules that are representative of a group (cluster) within this library. • Molecular characterization is based on 2D fragment descriptors consisting of a central atom and neighboring atoms connected to it within a predefined sphere size -- bonds between central and edge atoms. Groups of molecules are based on the structural similarity of fingerprints (bit strings of these fragments), and the centroid has the highest degree of similarity to other members of a cluster. Chemically unique compounds (singletons) with low similarity to other members of the collection are also identified. Sampling libraries are created from centroid and singleton selection along with augmentation with other members from the largest groups.

14. MyriaScreen • Superior structural diversity - Distinct drug-like properties MyriaScreen was created by combining medicinal chemistry expertise and decades of experience in compound acquisition from diverse sources. TimTec’s proprietary software was used to filter a pool of over 300,000 TimTec and Sigma-Aldrich compounds on the basis of diversity. Additional filters were set to consider MW (>225 and <600), cLogP, H-acceptor, H-donors, and rotatable bonds. Medicinal chemistry specialists refined the selection with great personal attention to remove compounds that were overly represented or not well suited for medicinal chemistry follow-up. MyriaScreen is rich in chemotypes and a valuable source of screening compounds for lead discovery. • Ready-to-use format - High purity - Efficient re-supply MyriaScreen is pre-plated for your convenience, 0.5 mg in 250 µL of DMSO per well. The compounds have an average purity > 95% with nothing below 90%. Should you require more material for follow-up, re-supply or re-synthesis is available. Although MyriaScreen is designed for use as a complete set, there are two alternative options to fit your purchasing needs. Compounds can be purchased as individual plates or cherry-picked and plated on a custom basis. • Formatting Options Available: The collection is pre-plated in 96-well plates and is available on request. There are 10,000 compounds, 0.5mg or 0.25mg per sample in DMSO solution. 0.5 mg in 250 mcL of DMSO is priced at $40,000.00  0.25mg in 125 mcL of DMSO solution is $24,500.00 0.05mg in 50 mcL of DMSO solution is $12,500.00 In pre-plated sets we have 1 and 12th columns empty.

15. Diversity Set It is our most popular competitively priced collection of 10,000 most diverse compounds selected from TimTec stock of over 120,000 compounds. Diversity Set is a superior collection in terms of diverse selection of singletons identified within variety of chemo types in TimTec stock: 2micromol or 1mg samples size in dry form is $53,000.00 5micromol or 2mg sample size in dry form is $64,750.00 0.5mg sample size is $31,000.00 1mg samples size is $47,000.00 On your request we can dissolve compounds in DMSO. Lead time applies. • ActiProbe10K, Diversity Set, and MyriaSreen Collection do not overlap in compound selection. Diversity Set is primarily diverse selection from our stock, variety of chemotypes is above all in focus. ActiProbe10K as entire collection strictly adheres to Lipinski rule of five, drug-likeness is in focus.

16. ApexScreen 5040 • ApexScreen is a collection of 5,040 compounds that were selected to represent the diversity of TimTec stock of over 120,000 compounds in a smaller format as opposed to larger general screening collections. ApexScreen in a variety of formatting options tailored to customer requirements is a perfect collection to jump-start any screening project. • ApexScreen was created with assistance of TimTec's Diversity Analysis Software that allows the assembly of libraries with maximized chemical diversity from databases of compounds that are currently available from TimTecUS and/or overseas stock. Diversity libraries can be further filtered to include molecules that fall within designated MW, cLogP and Lipinski Rule parameters. TimTec can also provide a selection of compounds from its databases which will include only those compounds that will contribute to the diversity of an existing customer library. • In addition to diverse selection of compounds that represent variety of chemotypes in TimTec general stock collection, ApexScreen includes a number of pure natural compounds from TimTec Natural Product Library to suit current trends in screening. • ApexScreen is a perfect collection for starting any screening project and a valuable addition to any existing compound library: • Various formatting option in terms of sample size or concentration are available: 5040 compounds: 0.5mg dry form, $16,800.00, Pre-plated in 96 well plates with removable tubes, rows 1&12th are empty. 0.25mg in DMSO, $11,500.00 0.1mg in DMSO, $8,600.00

17. Targeted Libraries • Molecules with molecular scaffolds found in agents reported in the technical/patent literature with the following biological properties: • Kinase modulation • GPCR binding • Protease inhibition • K-Channel Modulation • Anti-Infectives

18. H. Waldmann et al., J. Med. Chem., 46, 2917 (2003). NP Scaffold for a Series of Inhibitors in the Kinase Family An example: Comprising Targeted Library: ActiTarg-Series A compound library developed around nakijiquinones, natural inhibitors of the receptor tyrosine kinase called Her-2/Neu, produced analogs that inhibit two other receptor tyrosine kinases, VEGFR-3 and Tie-2.

19. ActiTarg Series Targeted Libraries • Our Kinase library, ActiTarg-K, includes over 6,600 drug-like compounds with low molecular weight that have the ability to inhibit protein kinases. This diverse kinase collection includes samples-analogs with chemical lattices that match the chemical lattices found in compounds with already tested kinase activities, which were reported in scientific literature. You can see the table of kinase and lattice types at: http://www.timtec.net/actitarg-k-kinase-modulators.html • GPCR ligands library, ActiTarg-G, currently has 2900 compounds. These agents possess chemical lattices present in compound types reported in the patent or chemical literature to have various kinase inhibitory activities, as described on our web site: http://www.timtec.net/actitarg-g-gpcr-ligands.html • To meet the interest and needs of investigators who are trying to identify low molecular weight, drug-like molecules with the ability to inhibit various proteases, TimTec has assembled a library of compounds with potential protease inhibitory activity, ActiTarg-P. These are about 2,000 compounds in the collection: http://www.timtec.net/actitarg-p-protease-inhibitors.html • Potassium Channel Modulators, over 800 cmpds: http://www.timtec.net/potassium-channel-modulators.html

20. ActiTarg-S, Serine Proteinase Inhibitors Library • Serine Proteinase Inhibitors Library collection includes analogs to a group of serine proteinase inhibitors (serpins) that are known to be similar in amino acid sequence and mechanism of inhibition, yet differentiate in their specificity toward proteolytic enzymes as it is reported in technical literature. • For instance, the groups of known serpins among others include: alpha 1-antitrypsin, angiotensinogen, ovalbumin, antiplasmin, alpha 1-antichymotrypsin, thyroxine-binding protein, complement 1 inactivators, antithrombin III, heparin cofactor II, plasminogen inactivators, gene Y protein, placental plasminogen activator inhibitor. • TimTec collection currently includes about 450 close analogs to known serpins. Entire collection in 1mg is $28.00 per compound. We may also select top diversity compounds and arrange them into plates: 80 compounds in 0.5mg size plated in 96-well plates with removable tubes, columns 1 & 12 left empty: 3 plates, 240cmpds is $4,560.00 4 plates, 320cmpds is $5,920.00 5 plates, 400cmpds is $7,300.00

21. Fragment-Based Library • Low molecular weight • Low binding affinity to a drug target • High solubility • clogP <= 3 • Rotable bonds <=5 • HBA <=3 and HBD<=3

22. Privileged Structure Library • Evaluation of the structures of pharmaceuticals and agents with good pharmacological activity led to identification of molecular substructures frequently associated with a higher level of biological activity. • These motifs were given the "privileged" label when they were found to be present in molecules that were active at two or more different receptors. • Aza-(and diaza-)biphenyls • Benzhydryl compounds • Biphenyls • Dihydropyridines • Anilino-pyridine, pyrimidine, or triazines • Phenylpiperazines • Flavonoids

23. Natural Product Library • Diversity by nature • Purity by science • Value by design Natural Product Librarynow includes 480 pure individual natural compounds: From Rediscovering Natural Products article published in Chemical and Engeneering News, why the interest in natural compounds is increasing: 1) Combinatorial chemistry's promise to fill drug development pipelines with de novo synthetic small-molecule drug candidates is unfulfilled 2) The practical difficulties of natural products drug discovery are being overcome by advances in separation technologies and in the speed and sensitivity of structure elucidation 3) A compelling case is being made for the intrinsic utility of natural products as sources of drug leads. TimTec has assembled a library of natural products and naturalproduct-derived compound that provide a broad selection of molecularframeworks that probe chemical diversity space. • Solids or freshly prepared DMSO solutions: 0.5mg set is $5,500.00 1mg set is $7,850.00 2mg set is $11,450.00 3mg/$14,950.00 0.05mg in 25 microliters of DMSO is $ 1,750.00 0.1 mg in 50 microliters of DMSO is $2,750.00 0.25 mg in 125 microliters of DMOS is $3,975.00 0.5mg in 250 microliters of DMSO is $5,500.00

24. Natural Product Derivatives • Several thousand NP-derived compounds are available in stock • A selection of about 4000 compounds has been assembled to provide a representation of the diversity of this collection • Price depends on the number of compounds selected and a sample size. Please inquire a quote.

25. Plant Extracts • About 9000 cataloged plants from various regions of the former USSR are available for collection • About 2500 dried plant species are in stock • Extracts are available on large scale • Fractionation and active component identification services are possible

26. Custom Library • TimTec can comprise compound collection of different size (from few to thousands of compounds) utilizing proprietary software based on variety of custom criteria: structure similarity search, presence of a particular fragment/s, defined MW, clogP, number of HBA and HBD, Lipinski Rule, Rule of 3, etc. • TimTec can also provide a selection of compounds from its databases which will include only those compounds that will contribute to the diversity of an existing customer library. We will do database comparison and diversity analysis. • Please contact us to discuss customization options.

27. Additional Notes • Price on compound libraries and custom selected collections including cherry-picking would depend on the number of compounds selected and a sample size. • Custom formatting options are available for all of our libraries. Please refer to the compound management/handling section of this presentation. • Prices do not include shipping and cost of custom containers • All compounds we have are stored in dry form and can be freshly prepared in DMSO. • Purity of compounds in our collections, on average is >/= 95% as determined by high-field 1H-NMR and/or MS. Overall purity is at least 90%. • Compounds are available for re-supply from stock or after re-synthesis depending on amounts required. Exact amount available for re-supply will be confirmed at the time of re-order. • TimTec does not hold any IP rights on compounds we sell. Once a hit is identified it is yours for further development.

28. TimTec Services • Compound Management • Consolidated Compound Procurement • Database management • Computational Services • Custom Synthesis • Analytical

29. Delaware Technology Park • Large scale project support

30. Sample Handling Services • Custom weighing in dry form or freshly prepared in DMSO • Preparation of storage, master and daughter (96-384 well) plates • Barcode labeling using chemically resistant labels • Conversion of existing libraries into HTS format • Freezer storage of dissolved compounds and overnight shipment under dry ice • Delivery of vials in 96-divider boxes Consolidated Compound Acquisition • Multi-source database mining • Single point-of-service ordering • Preparation of appropriately formatted plates • Uniform database processing • Database management • Possible vendor-to-vendor discounts

31. Sample Packaging

32. Analytical Services • LC/MS at TimTec location • LC/GC/MS and HPLC: Currently partnering with StereoChemicals in Delaware. • 500 MHz instruments: available in US (Ohio State University) to spot-check samples as needed • High-throughput NMR: a high capacity network (Moscow) of six instruments, 300 to 500 MHz, produces spectra in electronic (FID) and/or hard copy files

33. Computational Services • Vendor Database Acquisition and Management (e.g., duplication and availability determination) • Functional Group and Fragment Filtration • Lipinski Parameter Assessment • Library Comparisons (in-house vs. vendor) • Database Clustering • Database Comparison and Sorting by Diversity • Prediction of lipophilicity (LogP and LogD)

34. Diversity Analysis of an External Library compared to an In-house Screening Collection • Size of in-house library: 561,633 compounds • Size of vendor library: 133,622 compounds • Duplicates identified: 6810 compounds • Number of compounds that will maximize diversity of collection: ~65,000

35. TimTec Clients • TimTec has served more than 700 pharmaceutical, biotech and academic clients. • To name a few:

36. Contact TimTec • For more information please visit www.timtec.net • Contact: 1-800-574-7391; 1-302-292-8500 • Email: info@timtec.net