REVIEWS Drug Discovery Today  Volume 16, Numbers 7/8 April 2011
Review
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IEWIn silico repositioning of approved drugs
for rare and neglected diseases
Sean Ekins1,2,3,4,, Antony J. Williams5,
Matthew D. Krasowski6 and Joel S. Freundlich7
1Collaborations in Chemistry, 601 Runnymede Avenue, Jenkintown, PA 19046, USA
2Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010, USA
3Department of Pharmaceutical Sciences, University of Maryland, College Park, MD 21201, USA
4Department of Pharmacology, University of Medicine & Dentistry of New Jersey, Robert Wood
Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
5 Royal Society of Chemistry, 904 Tamaras Circle, Wake Forest, NC 27587, USA
6Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
7Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
One approach to speed up drug discovery is to examine new uses for
existing approved drugs, so-called ‘drug repositioning’ or ‘drug
repurposing’, which has become increasingly popular in recent years.
Analysis of the literature reveals many examples of US Food and Drug
Administration-approved drugs that are active against multiple targets
(also termed promiscuity) that can also be used to therapeutic advantage
for repositioning for other neglected and rare diseases. Using proof-of-
principle examples, we suggest here thatwith current in silico technologies
and databases of the structures and biological activities of chemical
compounds (drugs) and related data, as well as close integration with in
vitro screening data, improved opportunities for drug repurposing will
emerge for neglected or rare/orphan diseases.
Introduction
Neglected diseases are primarily tropical infections common in Africa, Asia and the Americas.
Infections with Mycobacterium tuberculosis (Mtb) or Plasmodium spp. are often included as
neglected diseases and are estimated to kill over two million people annually [1]. Recent studies
also suggest that over two billion individuals are infected with Mtb alone [2] and this represents
approximately one-third of the global population. These statistics highlight the enormous
economic and healthcare challenges for the countries and governments affected.
There are also thousands of diseases that occur in small patient populations and are not
addressed by any existing treatments (http://rarediseases.info.nih.gov/Resources/Rare_Diseases_
Information.aspx). These diseases are classified as rare or orphan diseases. Traditionally, such
diseases have not been the focus of big pharmaceutical company research as they have small
patient populations in industrialized countries that make it difficult to market drugs that recoup
Sean Ekins
Sean Ekins is Principal
Consultant for Collaborations
in Chemistry and
Collaborations Director at
Collaborative Drug Discovery
Inc. He has written over
160 papers and book chapters
on topics including drug–drug
interaction screening, computational absorption,
distribution, metabolism, and excretion (ADME)/Tox,
collaborative computational technologies and neglected
disease research. Dr Ekins graduated from the University of
Aberdeen, where he received his MSc, PhD and DSc.
Antony J. Williams
Antony J. Williams is Vice
President, Strategic
development for ChemSpider
at the Royal Society of
Chemistry. Dr Williams has
written chapters for many
books and has authored or
peer reviewed over 100 papers
and book chapters on nuclear
magnetic resonance (NMR), predictive ADME methods,
internet-based tools, crowd-sourcing and databasecuration.
He is an active blogger and participant in the internet
chemistry network. Dr Williams graduated with a PhD in
chemistry as an NMR spectroscopist.
Matthew D. Krasowski
Matthew D. Krasowski is a
board-certified clinical
pathologist and currently is
Clinical Assistant Professor and
Assistant Director of Clinical
Laboratories at the University
of Iowa Hospitals and Clinics.
His research interests include
nuclear hormone receptor regulation of drug
metabolism and computational approaches to
modeling receptors and immunoassay cross-reactivity.
He graduated with an MD and PhD in Neurobiology
from the University of Chicago.
Joel S. Freundlich
Joel S. Freundlich is a senior
research scientist in
Biochemistry and Biophysics at
Texas A&M University and a
visiting professor in Medicinal
Chemistry at Rutgers University.
His research interests focus on
seeding tuberculosis and malaria
drug discovery through the study of small molecules that
modulate essential biochemical targets. He received his PhD
in organic chemistry from the Massachusetts Institute of
Technology and then spent ten years in the pharmaceutical
industry before returning to academia.
Corresponding author. Ekins, S. (ekinssean@yahoo.com), (sekins@collaborativedrug.com)
298 www.drugdiscoverytoday.com 1359-6446/06/$ - see front matter  2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2011.02.016

 
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WOne approach to speeding up drug discovery is to find new uses for
existing approved drugs. This is termed ‘drug repositioning’ or
or structural similarity to eukaryotic targets, in this case the
bacterial and eukaryotic kinomes. The Pfizer researchers proposed
www.drugdiscoverytoday.com 299the cost of research and development and that are then profitable
over the long term. Consequently, drug discovery for neglected and
rare diseases has occurred mainly in biotech companies and acade-
mia. Rare diseases usually have small patient populations, although
there is no global agreement on what this size is. In the USA, a rare
disease is described as one that affects less than 200 000 people.
Some estimates suggest that this represents over 7000 rare diseases
affecting 25–30 million people [3] or 5000 patients per orphan
disease, with approximately 4000 orphan diseases needing treat-
ment [4]. Such a ‘small’ market size would make drugs for these
diseases less marketable compared with common diseases, such as
cancers, cardiovascular disease and diabetes, with sufferers treated
numbering in themillionsannually.However, somehave suggested
that profits can be made on smaller patient populations in a perso-
nalized medicine strategy and have called for more academia–
pharma collaborations that are focused on rare diseases [4].
There are considerable challenges with regards to clinical
research applied to rare diseases. Even though over 300 orphan
drugs have been approved since the passage of the US Orphan
Drugs Act in 1983, there is still a long way to go until most rare
diseases have a treatment [3,4].
Neglected and rare diseases as an attractive area for
pharmaceutical companies
Pharmaceutical companies are beginning to view rare or neglected
diseases as an opportunity to bring in more revenue as well as to
improve public relations. Developing treatments for rare or
orphan diseases might necessitate a smaller investment upfront
as, for example, in-licensing deals for an advanced therapeutic
candidate targeting this area are usually less costly than the typical
US$100s of millions for licensing drugs for other diseases (http://
www.crdnetwork.org/blog/big-pharma-moves-from-blockbusters-
to-niche–busters/). Recently, GlaxoSmithKline (GSK) made some
relatively small investments in rare diseases (http://cenblog.org/
the-haystack/2010/10/gsk-highlights-rare-diseases–approach/);
Pfizer (http://www.xconomy.com/boston/2010/09/01/pfizer-
gobbles-foldrx-in-big-pharmas-latest-rare-disease-play-in-boston–
area/) and several other large pharma companies, as well as the
World Health Organization, have been working together, invest-
ing US$150 million in research into neglected disease treatments
(http://thebigredbiotechblog.typepad.com/the-big-red-biotech-
blog/2010/10/big-pharma-and-governments-put-up-150-m-to-
fight-neglected–diseases.html).
These efforts might only be the tip of the iceberg, and more
substantial investments are likely to follow in the near future to
solidify the trend. These investments by pharma for rare diseases
are in addition to their significant investments in neglected or
tropical diseases represented by the GSK Tres Cantos facility
(http://www.gsk.com/collaborations/tres-cantos.htm), the Novar-
tis Institute forTropicalDiseases inSingapore (http://www.novartis.
com/research/nitd/index.shtml), the Lilly MDR-TB Partnership
(http://www.lillymdr-tb.com/), the Lilly TB Drug Discovery Initia-
tive (http://www.tbdrugdiscovery.org/) and The Critical Path to TB
Drug Regimens (http://www.tballiance.org/cptr/).
Drug repositioning
Drug Discovery Today Volume 16, Numbers 7/8 April 2011‘drug repurposing’, and traditionally has occurred by serendipity
[5]. Another strategy is to look at combinations of approved drugs
in the hope of finding synergy [6,7], an approach that has found
some success in cancer, HIV and Mtb treatments. In the neglected
and rare disease space, predominantly academic researchers have
looked at repositioning compounds that are already approved for
other indications (see references in Table 1 and Table 2). Drug
repositioning has been reviewed extensively in the context of
finding uses for drugs applied to major diseases, such as obesity
and Parkinson’s disease [4]. Well-known examples include drugs
such as thalidomide, sildenafil, bupropion and fluoxetine, which
found new uses beyond their initially approved therapeutic indi-
cations [5]. The example of thalidomide specifically suggests that
drugs that were originally withdrawn by manufacturers or
removed by the US Food and Drug Administration (FDA), or other
regulatory organizations, can be resurrected. Thalidomide was
notorious for causing birth defects if taken during the first trime-
ster of pregnancy. However, this adverse effect is not a major issue
in the novel use of thalidomide in treating multiple myeloma, a
disease that is not common in women of child-bearing age.
Benefits for pharma
For pharmaceutical companies, repositioning has significant com-
mercial value as it extends the markets for a compound and finds
new uses for shelved compounds at lower financial risk and in a
shorter time [8]. There has also been much discussion about how
different approaches to repositioning could work, but these have
not focused specifically on neglected diseases [5,9]. Others have
proposed that repurposing could be an invaluable tool for
neglected diseases [10]. The benefits of repositioning include:
working on known druggable targets, the availability of materials
and data (such as on long-term toxicology studies) that can be used
and presented to regulatory authorities; and, as a result, the
potential for a significantly more time- and cost-effective research
and development effort than typically seen with bringing a new
molecular entity to market.
Repositioning for neglected infectious diseases
In both the major-market and neglected infectious disease realms,
the rapid emergence of multidrug-resistant strains of pathogenic
microorganisms provides a sense of urgency to identify new scaf-
folds for antibiotics quickly. This is likely to require the explora-
tion of chemical space beyond known active antimicrobial
compounds. Pharma urgently needs new hits to initiate com-
pound optimization studies. However, productivity of novel anti-
biotic classes over the past 30–40 years has been extremely low and
this is exacerbated by the relatively low hit rates from high-
throughput screening (HTS) and secondary screens [11]. Several
new scaffold search efforts have been recently reviewed [12]. For
example, Pfizer has shown that pyridopyrimidine compounds
derived from a eukaryotic protein kinase inhibitor pharmacophore
were effective against gram-negative pathogens following whole-
cell screening [13]. The approach is an example of screening library
repurposing (counterbalancing the pessimism derived from
recently reported antibacterial-targeted screening efforts [11])
and illustrates the pursuit of bacterial targets with high sequence
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