1 Risorse bioinformatiche comunemente utilizzate nel processo di drugdiscovery ; esperimento di screening farmaceutico. Alessandro Provenzani Lab of genomic screening
2 Escursione storica Drug discovery Esempi farmaci moderni Processo immissione nel mercato Conclusioni
3 3000 a.c. Tavolette Sumere, indicazioni sulle operazioni galeniche, estratti acquosi o oleosi. Nessuna indicazione sulle quantità, pesi, misure. Tradizione orale? 1550 a.c. papiro di Ebers, di Hearst, tutto rigorosamente misurato estratti acquosi o oleosi. Medicamenti a base di birra, latte vino. 600 a.c. Romani, pratica medica, influenzata dagli etruschi, accompagnata da formule magiche e invocazioni alle divinità. Casta sacerdotale era dedita alla Ars Divinatoria consiste nell interpretazione di segni e presagi offerti dalla natura 460 a.c. Ippocrate, ideatore della medicina razionale, distacco dalla figura del medico-sacerdote. Inizio dell osservazione clinica obiettiva. primumnon nocere : il medico deve essere parco nella somministrazione dei medicamenti teoria medica dei quattro umori : sangue (cuore), flemma (cervello), bile (fegato), atrabile (milza)
4 Armamentario: elleboro nero, coloquintide, veratro bianco, oppio, belladonna, scilla Atropa Belladonna: pianta ricca di alcaloidi, più importante è l atropina, anticolinergico tutt ora utilizzato in clinica e anche improbabili come cervello di cane, sterco di capra, cuore di avvoltoio
5 300 a.c. Arrivano a Roma i medici Greci professionisti 40 d.c. Roma imperiale, tentativi di catalogare e raccogliere la farmacologia sono ad opera di Celso, classificazione delle forme farmaceutiche e medicamenti utilizzati in riferimento alle patologie. 37 libri della NaturalisHistoriadi Plinio sono registrate 119 piante ad uso medicinale e descrive la Teriaca del re Antioco. 129 d.c. Galenomedico di corte di Marco Aurelio, influenzò tutto il medioevo con i suoi trattati Nascono le prime forme di pubblicità per i medicamenti I Cirenaici (Libia) impressero sulle loro monete la pianta del Silfioe veniva usato come panacea per molte malattie Estinzione della pianta
6 d.c. Il mantenimento del sapere in occidente è affidato ai monasteriche mantengono gli scritti di Galeno, Ippocrate, Plinio. Nasce l Orto dei Semplici e l Armarium Pigmentarium(Spezeria del convento) XV-XVII secolo PhilippusAureolusTheophrastusBombastusvon Hohenheim detto Paracelso, alchimista fondatore della iatrochimica il vero scopo della chimica non consiste nella fabbricazione dell oro, ma nella preparazione delle medicine La malattia è uno squilibrio chimico del corpo che può essere ristabilito attraverso l uso di altre sostanze chimiche. Scopre il Laudano Nasce l attenzione verso il principio attivo del preparato farmaceutico Comincia la rivoluzione scientifica: momento di rottura con la tradizione medievale Newton, Keplero, Galilei, Pascal, Boyle anche in medicina e biologia: scoperta di batteri e protozoi (Van Leeuwenhoek) dimostrazione della falsità della generazione spontanea (Francesco Redi): nessun organismo si genera spontaneamente, ma ognuno nasce da altri esseri viventi della sua stessa specie Pasteur dovette ridimostrare, un paio di secoli dopo, la falsità della teoria
7 XVIII secolo Lavoisierpone le basi della chimica moderna introducendo il metodo scientifico e la necessità di determinazioni quantitative e riproducibili Nasce la chimica farmaceutica con Scheelecon l identificazione di molecole di interesse biochimico e farmaceutico, Withering individua nelle foglie della digitale una sostanza con proprietà cardiotoniche 1775Priesltycon il protossido di azoto gas ad azione esilalaranteed anestetica, che viene ripreso il secolo successivo dal dentista Wells che però non ebbe seguito Morton, amico e collega di Wells nonché studente, fece una dimostrazione utilizzando etere per l asportazione di un tumore mandibolare Nasce l anestesia in camera operatoria
8 XIX secolo Comincia il boom della chimica farmaceutica grazie all isolamento e la purificazione dalle piante medicinali dei principi attivi Inizia un processo di ricerca e produzione di nuove molecole su vasta scala, nascono i legami con la botanica, microbiologia, farmacologia Vengono definiti gli alcaloidi, molecole con caratteristiche basiche presenti nelle piante medicinali Vengono isolati in rapida successione morfina, emetina, stricinina, atropina, caffeina, chinina, codeina etc Passaggio da preparati galenici classici, parzialmente efficaci e spesso tossici, a forme farmaceutiche rigorose capaci di provocare un effetto costante e riproducibile Nascono le aziende farmaceutiche
11 Drug definition What are drugs Drugs are strictly defined as chemical substances that are used to prevent or cure diseases in humans, animals and plants. The activity of a drug is its pharmacological effect on the subject, for example, its analgesic or β-blocker action. Drugs act by interfering with biological processes, so no drug is completely safe. All drugscan actaspoisonsiftakenin excess. Forexample, overdosesofparacetamolcan cause coma and death. All substances are poisons: there is none which is not a poison. The right dose differentiates a poison and a remedy. Paracelsus( ) Furthermore, in addition to their beneficial effects, most drugs have non-beneficial biological effects. Aspirin, which is commonly used to alleviate headaches, may also cause gastric irritation and bleeding.
12 Lead compund LEADS Pharmaceutical chemists do not synthesise compounds at random. They usually start with a so-called lead compound (ie a compound which leads them onward), and make and test compounds with structures closely related to it. This lead compound will have shown some activity as a drug and the chemists hope that they can find a derivative of it which is better is more effective as a drug,hasfewersideeffects,ischeapertomakeetc. Agoodexampleoftheleadcompoundapproachisthedevelopmentofthedrug aspirin:
15 receptors and ligands John Langley in 1905 he proposed that so called receptive substances in the body could accept either a stimulating compound, which would cause a biological response, or a non-stimulating compound, which would prevent a biological response. It is now universally accepted that the binding of a chemical agent, referred to as a ligand,toasocalledreceptorsetsinmotionaseriesofbiochemicaleventsthatresultin a biological or pharmacological effect: concept of drug molecolar target
16 structure complementarity and pharmacophores Furthermore, a drug is most effective when all or a significant part of its molecular shape and electron distribution (stereoelectronic structure), is complementary with the stereoelectronic structure of the receptor responsible for the desired biological action. The section of the structure of a ligand that binds to a receptor is known as its pharmacophore. It is now believed that side effects can arise when the drug binds to either the receptor responsible for the desired biological response or to different receptors.
17 Lead identification: essential steps The first problem in drug discovery is the drug target identification Much of the effort of basic biomedical research is oriented towards the characterization ofapathology,howandwhyitcomesout,andwhichareitsspecificmolecolarfeatures The most popular approach to drug design by synthesis is to start with the pathology of the diseased state and determine the point(s) where intervention is most likely to be effective.
18 Drug Design
19 Me-too drugs The cost of introducing a new drug to the market is extremely high and continues to escalate. One has to be very sure that a new drug is going to be profitable before it is placed on the market. Consequently, the board of directors decision to market a drug or not depends largely on information supplied by the accountancy department rather than ethical and medical considerations. One way of cutting costs is for companies to produce drugs with similar activities and molecular structures to their competitors. These drugs are known as the me-too drugs.
20 Serendipity and side effects Chain and Florey s choice turned out to be very fortunate. Because of its efficacy and lack of toxicity, penicillin made the most compelling case for antibiotics in general
21 Lead identification: essential steps After an appropriate molecular target is identified, the next major task in the drug discovery process is generation and optimization of lead compounds Identification of lead compounds requires: Developing appropriate screening assays Binding affinity Efficacy Specificity Toxicity Screening molecule libraries containing potential lead compounds Natural product libraries Existing compound libraries Combinatorial chemistry libraries Virtual libraries
22 Lead identification Today, many discoveries start with biological testing (bioassays or screening programme) by pharmacologists of the potential sources in order to determine the nature of their pharmacological activity as well as their potencies. These screening programmes may be random or focused.: In random screening programs all the substances and compounds available are tested regardless of their structures. The random screening of soil samples, for example, led to the discovery of the streptomycin and tetracycline antibiotics as well as many other lead compounds. Random screening is still employed, but the use of more focused screening procedures where specific structural types are tested is now more common.
23 Lead identification: high-throughput screening The goal of HTS (High-Throughput Screening) is to accelerate drug discovery by screening large libraries often composed of hundreds of thousands of compounds(drug candidates) at a minimal rate of 20,000 compounds per week. For a number of years, HTS assays have been run in the standard 96-well microplate (working volume of up to 250 µl). The current goal of most companies is to move beyond this format to higher- density, lower-volume formats (e.g., 384- and 1536-well microplates). There are two primary advantages of these formats: increased throughput and lower volume, which translates into lower cost.
24 Lead identification: high-throughput screening Generally speaking, first-pass HTS assays(the primary screen) are less quantitative than traditional biological assays. Often, compounds are only tested in duplicate (an increasing number of companies are using singlets), and usually at one concentration (most often in the 1 10 µm range for combinatorial chemistry libraries). If a hit (positive) is discovered, more accurate secondary assays are used for elucidating the biological role and dose-response curve calculation. Analogues are made of the most promising of these compounds and they in turn are subjected to the screening procedure. This sequence of selective screening and synthesis of analogues may be repeated many times before a potentially useful drug is found.
25 Drug Design The design cycle describes the optimization of a lead strucutre to one or several development candidates. It is and iterative process with evolutionary character
26 Lead identification: High-throughput screening Screening perhaps millions of compounds in a corporate collection to see if any show activity against a certain disease protein
27 Lead identification: advent of systematic screening Development of automation and in vitro high-throughput biological screens has had a dramatic impact on lead discovery. Molecular biology has provided the tools for identification and validation of therapeutic targets, cloning and expression of sufficient protein to accommodate high-throughput screening, and determining the impact of elimination of the therapeutic gene by knock-out mutations.
28 Lead identification: screening methodologies Receptor screening methodologies can be based on either the determination of a functional response (e.g. cell proliferation) or on the interaction of a ligand with its receptor. There is a trend towards the development of cell-based assays (e.g. to replace animal studies), which has been facilitated by recombinant DNA technology using reporter gene systems. Binding of a ligand (agonist or antagonist) to its cognate receptor is the initial and indispensable step in the cascade of reactions that finally cause a pharmacological effect and many successful and widely used techniques are thus based on measuring ligand binding.
31 Sources of drugs Once the ability to screen libraries developed, the pressure on medicinal chemists increased to generate large quantities of compounds for screening. It originally started with drugs and lead compounds derived from natural sources, such as animals, plants, trees and microorganisms. Marine sources were not utilized to any extent until the mid-20th century. Today, natural sources are still important, but the majority of lead compounds are Today, natural sources are still important, but the majority of lead compounds are synthesized in the laboratory. The nature of these synthetic compounds is initially decided from a consideration of the biochemistry of the pathogenic condition.
32 Natural sources Naturalsourcesare stillimportantsourcesofleadcompoundsand newdrugs. However, the largediversityofpotentialnaturalsourcesin the world makesthe techniqueofrandomscreening a highlyempiricalprocess. The screening oflocalfolk remedies(ethnopharmacology) offersthe basisofa more systematic approach
33 powerful analgesic, about 200 times more potent than morphine potent neurotoxin
34 The principal alkaloid in opium and the prototype opiate analgesic and narcotic. A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent its primary therapeutic use is in the treatment of gout An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug An alpha-and beta-adrenergic agonist that may also enhance release of norepinephrine
35 Lead compounds broad-spectrum antibiotic produced by the streptomyces bacterium Antibiotic derived from the actinobacterium Streptomyces griseus. cholecistokinin
36 Natural sources Once screening identifies a material containing an active compound, the problem becomes one of extraction, purification and assessment of the pharmacological activity. However, the isolation of useful quantities of a drug from its land or sea sources can cause ecological problems. The promising anticancer agent Taxol, for example, was originally isolated from the bark of the Pacific yew tree. However, the production of large quantities of Taxol from this source would result in the wholesale distruction of the tree (six 100 year old trees for a patient), a state of affairs that is ecologically unacceptable. Let s trynottodo ascirenaici withsilfio Anticancer agent
37 Lead identification: use of compound libraries Synthetic Compound libraries Using traditional methods of chemical synthesis the potential drug substances are synthesised one at a time, purified, and then, after their structures have been confirmed, are tested for their effectiveness as drugs.soitcouldtakemanyyearstobuildupsuchalibrary. Over the past few years several techniques called collectively combinatorial chemistry have been developed which enable chemists to prepare libraries of thousands of related compounds quickly. These techniques use automated methods called parallel synthesis
38 Lead compounds Figure 1 All new chemical entities, 01/ /2006, by source (N = 1184). Major Categories of Sources.The major categories used are as follows: B Biological; usually a large (>45 residues) peptide or protein either isolated from an organism/cell line or produced by biotechnological means in a surrogate host. N Natural product. ND Derived from a natural product and is usually a semisyntheticmodification. S Totally synthetic drug, often found by random screening/modification of an existing agent. S* Made by total synthesis, but the pharmacophoreis/was from a natural product. V Vaccine.
39 Drug chemical space
40 Rational design The MAGIC BULLET The search for the magic bullet has inspired scientific drug discovery from its very beginnings and has remained with this multidisciplinary endeavour ever since In drug research, with the growth of chemistry, pharmacology and other disciplines, the ideal of generating magic bullets or achieving exclusive and absolute specificity has been a constant aim. The switch from mechanism- to target-oriented drug discovery brought about by molecular genetics and genomics has recently re-established this ideal in a strict molecular context. Ideally, an agent should interact with one selected target, elicit a premeditated or intended response, disengage from the target and be metabolized and excreted without any further effects on the organism in question.
41 The market For the first time in decades, the oncology therapeuticarea hasovertakencardiovascular medicine as the leading revenue contributor A major reason for the rise of oncology as a revenue contributor comes from the success of bevacizumab(avastin), rituximab(mabthera/ Rituxan) and trastuzumab(herceptin) and of imatinib(glivec/gleevec)
42 Rational design GLEEVEC case Chronic Myeloid Leukemia (CML) The Philadelphia (Ph) chromosome is an abbreviated chromosome 22 that was shortchanged in an a reciprocal exchange of material with chromosome 9. This translocation occurs in a cell in the bonemarrow cell and causes CML On a molecular level the Philadelphia chromosome translocation results in the production of a fusion protein. A large portion of a proto-oncogene, called ABL, on chromosome 9 is translocatedto the BCR gene on chromosome 22. The two gene segments are fused and ultimately produce a chimericprotein that is larger than the normal ABL protein.
44 Chronic Myeloid Leukemia (CML) Modes of action
45 The core structure of the lead compound (black) The addition of a 3'-pyridyl group (blue) enhanced the cellular activity An amide group (red) provided activity against tyrosine kinases. A 'flag methyl' (purple) abolished the undesirable protein-kinase-c inhibitory activity The attachment of an N-methyl piperazinemoiety (green) markedly increased the solubility and oral bioavailability.
46 Docking of the molecule on the 3D structure of the Abl kinase Ribbon representation of the three-dimensional structure of Ablkinasedomain in complex with gleevec. The molecular surface of the inhibitor is shown. A central conserved region of the kinase, the catalytic segment, is shown in green and the activation loop in magenta.
47 Clinically, CML is a chronic disease that evolves through three successive stages, from the chronic phase to the end stage of blast crisis. Overall, the median survival time of patients with newly diagnosed CML is approximately 5 6 years.
49 The clinical development was particularly rapid, as can be seen by comparison with the typical drug discovery and development times shown in the inset. An NDA for Glivecwas submitted just two years and nine months after treatment of the first patient with CML, and FDA approval was given less than three months after application. CML, chronic myelogenousleukaemia; GIST, gastrointestinal stromaltumour; NDA, new drug application; PKC, protein kinase C.
50 Monoclonalantibodies: Molecular biomedical research identifies potential drug target EGFR and VEGFR signaling share common pathways. The network of both family receptors may control pathways that affect cell proliferation, survival, differentiation, and migration.
51 Antibodies Complex protein-based molecules produced by B lymphocytes that bind to and help to eliminate foreign and infectious agents in the body. Antibodies are Y shaped, having two sets of branches attached to a single stem. The arms of the Y (Fab) are the so called variable regions, the tips of the arms contain antigen-binding regions, and the stem (Fc) is a constant region. The constant regions trigger effectorfunctions (phagocytosis, cytolysis) by linking the complex to other cells of the immune system.
52 Monoclonalantibodies(mAbs) can be designed to selectively target tumourcells and elicit a variety of responses once bound. 206 therapeutic oncology mabsentered clinical study sponsored by commercial organizations between January 1980 and December 2005 (8.24/year). To date, 12 of these anticancer mabshave been approved for marketing in at least one country The success of mabsis due to the rapid identification of new molecolartargets and to the improvement of biotechnological methods for the production Originally, mabswere antibodies produced from a single B lymphocyte. mabsof a defined peptide sequence have identical antigen-binding regions and bind to the same site (the epitope) of an antigen.
54 Modes of action mabs are potentially capable of multiple functions. Themodeofdestructioncanbe Direct: carrying toxic material to the target via conjugated radioactive isotopes or toxins, or antibody triggered apoptosis Indirect: by activation of immune system components, blockade of critical receptors, Indirect: by activation of immune system components, blockade of critical receptors, sequestering growth factors or inducing apoptosis. In the case of soluble antigens, the mab should sequester the target.
55 Conjugated mabs can increase the specificity of chemo- or radiation therapy and improve the efficacy of immunotherapy, but have some drawbacks; they are more difficult to manufacture and may have greater safety issues compared with their naked counterparts.
56 Immunoconjugatesof various kinds constituted 44% of the total anticancer mabsin clinical study to date Most immunoconjugateshave been designed to carry a radioactive isotope (radioimmunoconjugates) or a toxin (immunotoxins). Immunotoxinscomposed of mabsthat are conjugated to a wide variety of either protein or small-molecule cytotoxinshave also been studied. 3 of the 12 are radiolabeled, 1 conjugated with immunotoxin For both type problems arise due to the lack of potency at the doses delivered to the tumour site
57 UnconjugatedmAbscan function through more than one mechanism, but a common primary mode of action is the destruction of targeted cells through activation of components of the human immune system. For example, after binding to a target, mabscan recruit effectorcells such as natural killer cells or macrophages to destroy the target Although all eight currently approved unmodified anticancer mabspotentially have the ability to function through activation of the immune system, only two rituximab(rituxan; Biogen Idec) and alemtuzumab(campath; Genzyme) are believed to use this way as their primary mode of action. The other six products function through alternative primary modes of action (blockade of growth factor receptor interaction, receptor downmodulationand inhibition of signalling). mabsare not necessarily restricted to a single mode of action. For example, trastuzumab(herceptin; Genentech) has been reported to induce immune system modulation as a possible alternative or additional mechanism to human epidermal growth factor receptor 2 (HER2) downmodulation
58 Efficacy The use of monoclonal antibodies is diffuse in cancer therapy Clinical responses varies from 15-50% of patients treated in clinical trials (partial or full response). Some MAbs have increased the efficacy of treatment of certain tumors, with acceptable safety profiles. Issues to be addressed include dosing strategies, timing, and schedule of antibody administration; duration of treatment; need for tailoring; and further testing under specific circumstances. The discovery of effective combinations with other biologic agents would be very useful. Multimodalityapproaches, basedon synergistic effects observed with the combination of antibodies with chemotherapeutic drugs and/or radiotherapy also merit further investigation
59 Tumor initiation For decades, tumour initiation and development has been regarded as a multistep process that is reflected by the progressive genetic alterations that drive the transformation of normal human cells into highly malignant derivatives. As cancers arise only after multiple mutagenic events, long-lived cells are probably the most capable of supporting such cumulative changes. Cancer cells are genetically instable It has been proposed that progressive genetic alterations might occur at the level of tumour-initiating cells, from which tumor originates (clonal progression)
60 Stem Cell features - undifferentiated - self renewal by asymmetric division -can divide without limit
61 Cancer Stem Cell features (acquired by mutations) - un (de) differentiated - self renewal by asymmetric division - can divide without limit
62 In normal tissues, the heterogeneity of cells reflects a hierarchical programme of differentiation in which multiple mature cell types are derived from a common multipotent stem cell through intermediate progenitors. Heterogeneous populations of cancer cells at various differentiation stages could be the result of both acquired mutations and aberrant but hierarchical differentiation programmes. Cancer is both a proliferation and a differentiation disease, and the 'clonal evolution' and 'cancer stem cell' models might not be mutually exclusive, as initially thought. Owing to genetic instability, the tumour-initiating cells isolated from a clinically detectable tumour would probably have a substantially different genetic profile from the initial transformed cells that originated the tumour.
63 Drug development Over 90% of drugs entering clinical trials fail to make it to market On average, it takes years to create a new drug The average cost to bring a new drug to market is estimated at $770 million
64 Drug discovery process 1 Drug Molecule patentable non-teratogenic 10,000 Drug Candidates Valid Biomedical Hypothesis? Statistics show that out of each 10,000 or so new molecules generated, only about one will ultimately survive the array of requirements necessary for a candidate molecule to become a drug that reaches patients
65 Drug development process 1 Drug Launch Cost-effective manufacturing Carcinogenicity studies 10 Drug Molecules The challenge continues in development
66 Drug development process Identify disease Isolate protein involved in disease (2-5 years) Find a drug effective against disease protein (2-5 years) Scale-up Preclinical testing (1-3 years) Human clinical trials (2-10 years) Formulation FDA approval (2-3 years)
67 The number of new drug approvals is decreasing and the cost for research and development is constantly increasing
68 -Drugdiscoverershaverecently been able to generate molecules that fulfill the demands of the magic bullet concept to a considerable degree -Conventionalcancerchemotherapy should be replaced step by step by targeted therapy illustrates what has already been achieved and indicates how drug therapy against cancer should develop overthe coming years -In spite of a growing sophistication in describing the molecular details of a particular target the ideal of designing drugs de novo or synthesizing tailor-made chemicals that fulfill all requirements of efficacy, tolerance and absorption, distribution, metabolismand excretion(adme) characteristics has remained elusive
69 The principleofthe magic bullet itself or, as we would say today, the concept of exclusivity in which a drug interacts with only one target at least in some multifactorial diseases, a drug with multiple wellchosen points of attack might be preferable to a drug with only one target, even if that target is crucial and its engagement by the drug in question absolutely specific Some authorshavethereforeadvocated a return to biology-driven strategies that expose drug candidates to more complex test systems Approachesofthistype might indeed help to select compounds that address a typical combination of targets, rather than a single molecular entity the so called magic bullets of the second order
70 Bibliografia: Per la parte storico-introduttiva: Il progresso terapeutico di ColapintoLeonardo, Annetta Antonino, AbocaEdizioni Per la parte scientifica: RenaudCapdeville, Elisabeth Buchdunger, JuergZimmermannand Alex Matter, NATURE REVIEWS DRUG DISCOVERY, JULY Jeffrey M. Rosen1 and Craig T. Jordan2, 26 JUNE 2009 VOL 324 SCIENCE, 1670 JaniceM. Reichertand ViiaE. Valge-Archer, NATURE REVIEWS DRUG DISCOVERY, VOLUME 6 MAY JürgenDrews, NATURE REVIEWS DRUG DISCOVERY, VOLUME 5 AUGUST FDA drugapprovals, NATURE REVIEWS DrugDiscovery, VOLUME 8 FEBRUARY David J. Newman* and Gordon M. Cragg, J. Nat. Prod. 2007, 70, Salestrendsbytherapeuticarea: , nature reviews DrugDiscovEry, volume 8 september Sales of biologics to show robust growth throughto2013 nature reviews DrugDiscovEry, volume 8 november Bin-Bing S. Zhou*, Haiying Zhang, Marc Damelin*, Kenneth G. Geles*, Justin C. Grindley* and Peter B. Dirks, nature reviews DrugDiscovEry806 october2009 VoluMe8
Principal Principal Investigator s Investigator Organization Project Title Alan Pollack University of Miami Integrated Biomarker Profiling for Individualized Prostate Cancer Therapy General Project Abstract
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