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02-FDA-PQRI Symp Oct ASPECTS OF THE DISCOVERY AND DEVELOPMENT OF PLANT- DERIVED DRUGS A. Douglas Kinghorn, Ph.D., D.Sc. Professor and Jack L. Beal Chair College of Pharmacy The Ohio State University Second FDA/PQRI Conference on Advancing Product Quality, North Bethesda, MD (October 5-7, 2015) OUTLINE OF PRESENTATION Rationale for the Search for New Drugs from Higher Plants. General Approaches to Drug Discovery from Tropical Plants in an Academic Environment. Development of Silvestrol from Aglaia foveolata (a Potential Anticancer Agent) and Pentalinonsterol from Pentalinon andrieuxii (a Potential Antileishmanial Agent). Summary and Conclusions. KEY QUESTIONS TO BE ANSWERED In natural product drug discovery screening programs in an academic environment, how, why, and when may highly promising compounds be identified? What types of collaborative investigations can then be pursued in order to develop these lead compounds further? RATIONALE FOR THE SEARCH FOR NEW DRUGS FROM HIGHER PLANTS SMALL-MOLECULE NATURAL PRODUCT BASED DRUGS (JANUARY 1, 1981 − SEPTEMBER 9, 2012) Total number of small molecule approved drugs world-wide was 1115 “N_all” refers to sum of N, NB and ND codes “S*_all” refers to sum of S* and S*/NM codes (Newman and Cragg 2012) NATURAL PRODUCT-DERIVED DRUGS INTRODUCED 2000-2008 Source Organism Type Number Terrestrial Plants 8 (apomorphine HCl, arteether, dronabinol/cannabidiol (mixture), galanthamine HBr, lisdexamfetamine, methylnatrexone Br, nitisinone, tiotropium Br) Terrestrial Microorganisms 24 (amrubicin HCl, anidulafungin, biapenem, caspofungin acetate, cefditoren pivoxil, ceftobiprole medocaril, daptomycin, doripenem, ertapenem, everolimus, fumagillin, gentumazumab ozogamicin, ixabepilone, micafungin Na, miglustat, mycophenolate Na, pimecrolimus, pitavastatin, retapamulin, rosuvastatin Ca, telithromycin, temsirolimus, tigecycline, zotarolimus) Marine Organism 2 (trabectidin, ziconotide) Terrestrial Animals 2 (bivalirudin; exenatide; synthetic versions of natural forms) [Chin et al., AAPS J., 8 (2), E239 (Article 28), 2006; http://www.aapsj.org; Butler, in Natural Product Chemistry for Drug Discovery, eds. A.D. Buss and M.S. Butler, RSC: Cambridge, U.K., 2010; p. 321] PLANT NATURAL PRODUCTS AND DERIVATIVES APPROVED BY THE U.S. FDA (2012 TO MID-2013) Natural Lead Year Generic Name Trade Name Indication Compound Ingenol-3- 2012 Ingenol mebutate Picato® Actinic keratosis angelate Lorcaserin 2012 Ephedrine Belviq® Obesity hydrochloride Omacetaxine Homoharring- Chronic myeloid 2012 Synribo® mepesuccinate tonine leukemia HIV/AIDS anti- Croton lechleri retroviral- 2012 Crofelemer oligomeric pro- Fulyzaq® associated anthocyanidins diarrhea ado-Trastuzumab 2013 emtansine (protein- Maytansinea Kadcyla® Breast cancer bound) Menopause- 2013 Ospemifene Phytoestrogens Osphena® associated dyspareunia aAlthough first isolated from a plant, maytansine is now regarded as a microbial product. GENERAL APPROACHES TO COLLABORATIVE DRUG DISCOVERY FROM TROPICAL PLANTS IN AN ACADEMIC ENVIRONMENT PLANT NATURAL PRODUCT DRUG DISCOVERY AND DEVELOPMENT Natural Products Discovery Medicinal Chemistry Molecular Modeling Target-based Bioassays Cell-based Bioassays Lead Identification In Vivo Bioassays Medicinal Chemistry Lead Optimization Combinatorial Chemistry Pharmacology, Toxicology Pharmacokinetics, ADME Lead Development Drug Delivery Drug Candidates Clinical Trials MAJOR STAGES IN NATURAL PRODUCT DRUG DISCOVERY Organism collection (after development of intellectual property agreements). Preparation of extracts (using standardized extraction scheme). Initial bioassays (cell-based and target-based). Biostatistics; data management; dereplication of leads; lead prioritization). Bioactivity-directed fractionation (= isolation of active compounds from biomass using a decision tree based solely on bioactivity). Structure elucidation of bioactive compounds. Scale up and analogue development of lead compounds. Advanced bioassays; data management, biostatistics). Lead optimization; pharmaceutical development. (Clark, In Foye’s Principles of Medicinal Chemisry, 5th Edn., Williams, D.A.; Lemke, T.L., Eds., Lippincott Williams & Wilkins: Baltimore, 2002, p. 24) CONVENTION ON BIOLOGICAL DIVERSITY (CBD) A treaty with 42 Articles dictating codes of behavior in the study and sustainable use of biological diversity (http://www.biodiv.org/). This was signed by >150 countries during the 1992 Earth Summit in Rio de Janeiro (“Rio Convention”). The U.S.A. signed in 1993, but never ratified this treaty. In practice, this means the government must follow the treaty, but there is no binding effect on private citizens. Source countries have sovereign right over their genetic resources (e.g., mutually agreed terms, prior informed consent, equitable sharing of benefits). (Cordell, in Natural Product Chemistry for Drug Discovery, eds. A.D. Buss and M.S. Butler, RSC: Cambridge, U.K., 2010; p. 81) NUMBERS OF ORGANISMS FOR DRUG DISCOVERY Eubacteria (bacteria), cyanobacteria (blue-green algae) 4,000a Archaea (halobacteria, cyanogens) 80,000 Protoctista (e.g., protozoa, diatoms, “algae”, including “red algae” and “green algae”) Plantae (mosses and liverworts, ferns, seed plants)b 270,000 Fungi (e.g., molds, lichens, yeasts, mushrooms)c 72,000 Animalia (e.g., mesozoa, sponges, jellyfish, corals, flatworms, 1,320,000 roundworms, sea urchins, mollusks, segmented worms, arthropods, insects, fish, amphibians, birds, mammals)d-f a Figures are species described taxonomically to date in each group. b Plants are the second largest group of classified organisms, representing 15% of the known biodiversity. c Only a relatively small proportion (5%) of the estimated 1.5 m fungi have been classified taxonomically to date. d The largest numbers of organisms are the arthropods, inclusive of insects (ca. 950,000 species). e Of the 28 major animal phyla, 26 are found in a marine environment. f Over 200,000 species of invertebrate animals and algal species occur in the sea. (Tan et al., Curr. Drug Targets 7, 265, 2006) SECONDARY METABOLITES FROM VASCULAR PLANTS (TRACHEOPHYTES; HIGHER PLANTS) Altogether there are an estimated 200,000 secondary metabolites (“natural products”) (Dixon and Strack, Phytochemistry 62, 815, 2003). Of these, the major groups are estimated as isoprenoids (ca. 80,000 compounds), phenolics (ca. 40,000 compounds), and alkaloids (ca. 30,000 compounds). More secondary metabolites have been isolated from plants than other types of organisms. An average leaf may contain >30,000 phytochemicals (Turi et al., J. Nat. Prod. 78, 953, 2015). Specialized defensive secondary metabolites are associated with higher plants, such as gallotannins, proanthocyanidins, and resveratrol oligomers. NUMBER OF NEW NATURAL PRODUCT COMPOUNDS PUBLISHED IN THE JOURNAL OF NATURAL PRODUCTS OVER THE DECADE 2005-2014a,b Terrestrial Terrestrial Terrestrial Marine / Otherse Microbes/ Plantsc Animals Aquaticd Fungi 1,869 7,760 117 3,138 33 (14.5%) (60.0%) (0.9%) (24.3%) (0.3%) a From a total of 12,917 new small-molecule compounds. Percentages of the total are shown in parentheses. b Annual totals of new compounds reported were: 2005, 1,200; 2006, 1,276; 2007, 1,269; 2008, 1,388; 2009, 1,505; 2010, 1,369; 2011, 1,303; 2012, 1,049; 2013, 1,156; 2014, 1,402. c Including higher and lower plants (vascular and non-vascular). d Including animals, microorganisms, and plants. e For example, propolis of different geographical origins. DEVELOPMENT OF SILVESTROL (A POTENTIAL ANTICANCER AGENT) AND PENTALINONSTEROL (A POTENTIAL ANTILEISHMANIAL AGENT) DRS. M.E. WALL (LATE) AND M.C. WANI: CO-DISCOVERERS OF TAXOL AND CAMPOTHECIN (Photograph by Jimmy W. Crawford, RTI) COLLABORATIVE PROJECTS ON THE DISCOVERY OF NATURAL PRODUCT ANTICANCER AGENTS National Cooperative Drug Discovery Group (NCDDG) Granta (U19 CA52956) (1990-1995; 1995-2000; 2000-2006) Program Project Grantb (P01 CA125066) (2007-2013; 2014-2019) Current Collaboration is between: The Ohio State University (OSU), Columbus, OH; University of Illinois at Chicago (UIC), Chicago, IL; University of North Carolina at Greensboro (UNC-G), NC; Mycosynthetix Inc., NC; Eisai Inc., Andover, MA Both grants funded by the United States National Cancer Institute, NIH a,bPrincipal Investigators: G.A.Cordell (UIC; 1990-1992); A.D. Kinghorn (UIC/OSU; 1992-present) [Most recent review: Kinghorn et al. , Pure Appl. Chem. 81, 1051, 2009] PLANT COLLECTIONS AT UIC (DRS. NORMAN FARNSWORTH AND DOEL SOEJARTO) Some tropical forests support more tree species in 0.5 km2 than in all of North America or Europe (Burslem, 2001). About 120,000 endemic species in tropical areas regarded as threatened due to massive habitat loss (Pitman & Jørgensen, 2002). Source countries have sovereign right over their genetic resources (e.g., mutually agreed terms, prior informed consent, equitable sharing of benefits). Anticancer Plant Collections 1990-2011 Total plant accessions obtained 6,599 Representing: 2,609 species 1,466 genera 222 families Over 200 recollections FORMER RAID PROGRAM OF THE UNITED STATES NATIONAL CANCER INSTITUTE Rapid Access to Intervention Development (http://dtp.nci.nih.gov/docs/raid/raid_index.ht ml). A program designed to facilitate translation to the clinic of novel, scientifically meritorious therapeutic interventions originating in the academic community. Contracts leading to preclinical development leading to filing of an IND. Required submission of a formal proposal and peer review. BETULINIC ACID: A NCDDG COMPOUND THAT ENTERED CLINICAL TRIALS AT THE UNIVERSITY OF ILLINOIS
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