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DRUG REPOSITIONING

DRUG REPOSITIONING

-Presented By Mr Parin Vora

16-07-20161

Contents:Introduction Need of Drug RepositioningSources of Drug RepositioningOn & Off target concept & approchesMethods of Drug RepositioningChallengesConclusionReferences

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Introduction : What is Drug Repositioning?

Recycling old drugs Drug repositioning also known as Drug repurposing, Drug re-profiling,Therapeutic Switching and Drug re-tasking

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Strategy of discovering new indications (uses) for existing drugs or biologics

The process of finding new uses outside the scope of the original medical indication for existing drugs

Eg: Sildenafil citrate (Viagra) - repositioned from a common hypertension and anginal drug to a therapy for erectile dysfunction.16-07-20164

Need of Drug RepositioningA repositioned drug does not need the initial six to nine years typically required for the development of new drugs, but instead goes directly to preclinical testing and clinical trials, thus reducing risk and costs.(Reduced development costs and time)

Longer life cycle and improved return on investment

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Increased success rates

Possibility of extending the patent life of a compound

Facilitating the identification of new targets for old drugs

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Sources Of Drug Repositioning

Drugs in clinical development for a different indication Drugs that failed to demonstrate efficacy for a particular IndicationDrugs that have been discontinued for commercial reasonsMarketed drugs for which patents are close to expire or when generic versions are already available and drugs which are not launched in large markets and half baked drugs

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On Target And Off Target Concept And Approaches Of Drug Repositioning:On target: Known pharmacological mechanism is applied to a new therapeutic indication. Eg Galantamine.

Off target: Looking for pharmacological mechanisms that is not described for a known molecule. Eg Astemizole.

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16-07-201611 There are two approaches for drug repurposing:1)Known compound new target2) Known target new indication

Methods/ Mechanism16-07-201612

A . Blinded search or screening methods

Do not include pharmaceutical or biological information & less likely to help elucidate any mechanisms of action of drugs

Most of them depend on serendipitous(by chance) identification from tests aimed at specific diseases and drugs

Advantage :high flexibility for application to a large number of drugs or diseases

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Eg :Sildenafil citrate (from angina,hypertension to erectile dysfunctioning) cGMP GMP

Vasodilator inhibited by Sildenafil

In angina & hypertension

Sildenafil inhibit PDE 5 not found in heart but found in erectile ( clinical trials) tissue of males( thus increase in blood flow) In erectile dysfunctioning16-07-201614PDE

B . Target-based methods

Comprise in vitro and in vivo high-throughput and/or high-content screening (HTS/HCS) of drugs for a protein or a biomarker of interest and in silico screening of drugs or compounds from drug libraries ie selection of drug according to targetSignificantly improve drug discovery because most targets link directly with the disease mechanismsEnable researchers to screen nearly all drugs or compounds with known chemical structure information : few days

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Eg : MLR 1023 ( from anti-ulcer to type II diabetes)

Tolimidone ( MLR 1023) In silico studies for

Antiulcer Target in type 2 diabetes

Lack of efficacy Target : selective Lyn Kinase activator

Development halted Improves: Glycemic control in vivo Drug- safe & well tolerated in clinical trials16-07-201616

C . Knowledge-based methods

Applying bioinformatics or cheminformatics approaches to include the available information of drugs, drugtarget networks , chemical structures of targets and drugs , clinical trial information (adverse effects) , signaling or metabolic pathways into drug-repositioning studies

Advantage : they include a large amount of known information into the drug-repositioning process to improve its prediction accuracy 16-07-201617

Eg : Simvastatin (antihyperlipidermic to breast cancer)

HMG CoA HMG CoA Reductase inhibited by Mevalonate simvastatin

Dolichol FPP GPP

Stimulatory effects Isoprenylation of on DNA synthesis intracellular G proteinsof tumor cells Ras & Rho

helps in tumor cell proliferation, differentiation,apoptosis

Down regulation of NFkB regulated antiapoptotic gene productsFurther clinical trials required demonstrate efficacy16-07-201618

D. Signature-based methods

Make use of gene signatures(a group of genes in a cell whose combined expression pattern is uniquely characteristic of a medical condition) derived from disease omics data with or without treatments, to discover unknown off-targets or unknown disease mechanisms

Advantage : useful to uncover unknown mechanisms of action of molecules and drugs

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Eg : Cimitidine (from pepticulcer : {H2 receptor antagonist} to lung cancer)Mechanism not clearly knownBut induces Fas and FasL gene expression on MDSC surface - apoptosis

13-09-201420

PRAPPRAPCaspase CaspaseFasFasLCimitidineApoptosisMDSCMDSC

E . Pathway- or network-based methods

Utilize disease omics data, available signaling or metabolic pathways, and protein interaction networks to reconstruct disease-specific path- ways that provide the key targets for repositioned drugs

Advantage : narrowing large number of proteins down to a specific network with a few proteins (or targets)

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Eg: Fasudil (from vasodilator to Alzheimers disease)16-07-201622Genetic variation of KIBRA protein: Alzheimer's disease

Rac vital protein : supports key cellular function

Activate protein Kinase-C Rho kinase enzyme (ROCK) inhibits KIBRA protein-no genetic variation/normal

Fasudil Hydroxyfasudil inhibits

A(Beta Amyloid)-induced neuronal damage : pathology of AD & Fasudil : reduces A burden thus preventing neuronal damage

F . Targeted mechanism-based methods

Utilize treatment omics data, available signaling pathway information and protein interaction networks to delineate (to find) the unknown mechanisms of action of drugs Advantage: Discover the mechanisms related to diseases or drugs and identify those directly related to treatments of drugs to specific diseases (which drugs given in which disease)

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16-07-201624Eg: Clomifene (from oligoovulation to breast cancer)oligoovulation(If ovulation is irregular, but not completely absent, this is called oligovulation)

Clomifene is a selective estrogen receptor modulator (SERMs) block the effects of estrogen in the breast tissue.

SERMs (clomifene)work by sitting in the estrogen receptors in breast cells

SERM in the estrogen receptor: there is no room for estrogen : can't attach to the cell

If estrogen isn't attached to a breast cell : the cell doesn't receive estrogen's signals to grow and multiply

Challenges:Choosing the right therapeutic areas for test drugs Studies: dependent on the prior knowledge and available information from specific studies: one can select and determine appropriate repositioning methods Evaluate carefully the available drug-repositioning methods :determine which is the best for that study Another issue for the available drug-repositioning studies for diseases with low knowledge have relatively low success rates16-07-201625

Conclusion: Drug repositioning method is less time consuming and less costly as compared to De novo drug discovery Increase in market competition, pharmaceutical companies are adopting less costly and less time consuming methods (speedy methods) to develop new drugs or to develop new uses from old drugsLarge number of drugs available for drug repositioning Advancement in technology :more and more drugs are in process of drug repositioning Thus: future drug repositioning may provide new treatment options for both common and orphan/rare diseases16-07-201626

References:

Drug Discovery Today _ Volume 19, Number 5 _ May 2014.Tobinick E.L. The value