Editorial
For reprint orders, please contact reprints@future-science.com
Network pharmacology for cancer drug
discovery: are we there yet?
“…network pharma­cology has allowed for a deeper understanding of these secondary
drug interactions, revealing that promiscuity often engages a synergistic combination of appropriate
high-value targets in cancer cells to produce treatment success.”
Keywords: bioinformatics n combination cancer drug discovery n de-risking drugs n network medicine n network pharmacology n synergistic drug
pairs n systems biology
In the era of targeted drug discovery, the major
thrust has been on designing small-molecule
drugs that show high binding affinity and speci-
ficity towards a druggable protein of interest [1] .
However, cancer is a complex disease arising
from alterations in multiple pathways (biologi-
cal/protein networks) [2] that have evolved to be
very robust [3] and designing drugs against single
proteins has yet to yield optimal clinical success
[4] . As they are fundamental organizing prin-
ciples of life, the removal of individual compo-
nents through single protein-targeted drugs from
such networks has surprisingly little functional
consequence, even in pathological states of can-
cer. Such robustness is commonly observed with
many other types of highly optimized large-scale
networks that have a general property to resist
change. To have an impact, interventions within
a biological network need to be multiple, but
highly selective. Most cancer drugs are designed
to target proteins having critical functions that
are structurally intricate and deeply seated in
complex networks. Predicting the functional out-
come of interventions, such as those originating
from drug treatment, is not as straightforward as
originally thought. So-called ‘targeted drugs’, no
matter how specific, are never chaste and usually
show promiscuous behavior, targeting multiple
ligands at the same time [5] – hence, both disease
understanding and drug discovery requires depar-
ture from a single protein or pathway-centric
approach to a more holistic multi-pathway or
network-centric approach [16] .
Recent advancements in molecular biology and
the emergence of integrated technologies, such
as systems biology, have allowed rapid assess-
ment of large expression datasets from cancer
patients. These strategies have partially aided
target-population stratification based on suscep-
tibility towards single or combination treatment
10.4155/FMC.12.44 © 2012 Future Science Ltd
regimens [6] . The emergence of network biology
has enhanced our knowledge of multi-pathway
interactions in cancer and helped to make sense
of drug-response signature datasets that collec-
tively decode the complex mechanisms of drug
action [7] . These holistic approaches have laid the
foundation for emerging concepts of ‘network
pharmacology’, which is solidifying its position
in cancer medicine. Unlike earlier reductionist
‘one drug, one target’ approaches, network phar-
macology invokes the idea that a drug engages Asfar S Azmi
with multiple targets and, in fact, rarely with a Department of Pathology, Wayne
single protein in isolation. Lacking the proper State University School of Medicine,
integrated tools, traditional molecular biology Karmanos Cancer Institute, 4100
John R, HWCRC Room 732,
pooled these secondary interactions as off-target Detroit, MI, USA
effects and many were categorized as toxic side Tel.: +1 3135768328
Fax: +1 3135768389
effects. Such a narrow view negatively impacted E-mail: azmia@karmanos.org
decisions regarding the clinical future of promis-
cuous drugs. However, network pharma­cology
has allowed for a deeper understanding of these
secondary drug interactions, revealing that pro-
miscuity often engages a synergistic combination
of appropriate high-value targets in cancer cells to
produce treatment success [8] .
Networks are amenable to ana­lysis using several
branches of mathematics. The most simple way
of representing a biological network is through
graph points, more commonly termed nodes or
vertices, which could be either genes, proteins or
even drugs connected by lines representing inter-
actions (called edges). Local and global proper-
ties of this map can be evaluated and neighboring
substructures or the role of adjacent nodes can
be inferred from information in patterns of con-
nections/interactions. This information can be
used to identify sets of high-value nodes, some of
which may serve as targets for drugs, depending
on the model of interest. Drugs generally exert
their effects through binding to proteins, thereby
modulating their activity. However, bioactive
Future Med. Chem. (2012) 4(8), 939–941 ISSN 1756-8919 939
Editorial | Azmi
compounds invariably influence more than one protein,
either: as a consequence of structural similarities between
the intended target and other proteins; through allosteric
effects on other proteins; through pleiotropic mecha-
nisms, where an interaction results in multiple down-
stream effects on other proteins; or through multivalent
target binding by different presentations of the active
molecule. Many prodrugs convert to active metabolites
and these are subject to an exponential range of possible
interactions within a target network or distantly unre-
lated network proteins. In whatever way these polyvalent
interactions occur, the end result is often unpredictable
efficacy or reduction in toxicity, or both. It is impor-
tant to know that the more highly specific and the less
promiscuous a drug is for a particular cancer target,
the more important that target must be in the cancer
network for it to have a significant effect.
“It is important to know that the more highly
specific and the less promiscuous a drug is for a
particular cancer target, the more important that
target must be in the cancer network
for it to have a significant effect.”
Network pharmacology takes into account all of the
aforementioned principles to optimize the efficacy and
safety of a candidate drug and their potent combinations.
The first component of network pharmacology is the
selection of optimal intervention points in the network(s)
of relevance to cancer subtype. Having extracted/curated
cancer-specific network data, combinatorial network
impact algorithms can be applied to calculate the opti-
mal combination of proteins targeting, which should
maximally affect the network(s) while inducing mini-
mal or acceptable modulation in healthy cell networks.
Such combinatorial impact analyses can be quantified
by many different integrated methods to evaluate how
much cancer network integrity can be changed by any
specific intervention. Since cancer-related networks typi-
cally relate directly to systems-level function or dysfunc-
tion, incorporating combinatorial impact in drug design
is predicted to influence the disease.
Many examples in the literature exist where network
pharmacology has been applied to cancer drug discov-
ery. The many applications of this technology include
identification of weak nodes in global cancer networks
[9] , predicting drug toxicity [10] , drug repurposing [11]
and identifying multi-scale mechanisms of drug action
[12] . In this direction, we were among the first to dem-
onstrate the application of network pharmacology in
the rational design of potent anticancer drug combina-
tions [13] . Recently, other groups have also performed
large-scale evaluations on synergistic pairs [14] . Network
940 Future Med. Chem. (2012) 4(8)
pharmacology has also been utilized to discover anti-
cancer effects of drugs developed for other disease. For
example, in a highly significant study, chemical systems
biology demonstrated that pleiotropic effects against
cancer cells by Nelfinavir, a potent HIV protease inhibi-
tor, was due to weak inhibition of multi-kinase activity
[15] . This example demonstrates the importance of this
highly promising field, still in its infancy. Key points in
this area that need extensive evaluation include:
n Obtaining network insights on optimally synergistic
combinations of targets, where optimality relates to
holistic network impact and not only to binding affin-
ity towards a single targeted protein;
n Selection of drugs that intervene upon the function of
weak links in the targeted pathway to exert the desired
effect through searching chemo­proteomic databases
for existing drugs with the desired binding and pleio-
tropic footprints, and use of reverse chemical engineer-
ing (i.e., generating novel compounds with predictive
multi-targeted footprints);
n Computation of the potential impact of proposed
compounds on normal cellular networks and selection
of most optimal drugs yielding maximum efficacy
with minimum effects on healthy cells.
“Network pharmacology is one such
advancement that holds promise to
revolutionize our approach towards
next-generation cancer drug design
and development.”
Drug discovery in the last two decades has pursued
a ‘black box’ approach in which the pharmaceutical
industry handpicked targets and focused on develop-
ing small molecules with the highest binding affinity
and specificity towards the identified protein of inter-
est. Such reductionist single protein/pathway-centric
approaches flooded the market with many promising
high-affinity drugs and these were rapidly pushed for
clinical evaluation. The cost of bringing one cancer
drug to the market ranges from US$2 to $4 billion.
These staggering numbers cover the cost starting from
high-throughput screening to identification of high-
affinity compounds, large-scale chemical synthesis of
candidate drugs, extensive pre­clinical evaluations in
different models, multispecies pharmacokinetic/tox-
icity profiling and finally, the most expensive, clinical
testing. Although such candidate drugs have strong
preclinical data supporting their anticancer potential,
they rarely pass the ultimate test at Phase II and III
clinical trials. The majority of these drugs either do
not translate their efficacy in patients or elicit seri-
ous and sometimes fatal adverse events, leading to
future science group
 Network pharmacology for cancer drug discovery: are we there yet?
their withdrawal because of incomplete understand-
ing of experimental evaluation or scientific explana-
tion. Thus, thousands of candidate molecules in the
laboratory are reduced to just a couple for clinical use.
This consistent failure indicates that the field of drug
discovery needs to be totally revamped in its approach
for designing newer molecules. Network pharmacology
is one such advancement that holds promise to revolu-
tionize our approach towards next-generation cancer
drug design and development. Skeptics have argued
that cancer is a heterogeneous biological process carry-
ing a number of variables, and drug behavior cannot be
predicted by mathematical or integrated network mod-
eling alone. Recently, researchers have appreciated the
power of integrated technologies, which has resulted
in multidisciplinary interactions between molecular
biologist and bioinformaticists, albeit, still with some
skepticism. Therefore, proponents of this technology
must be proactive in presenting convincing evidence
that promotes these emerging tools and rapidly merges
them into mainstream cancer drug discovery. These
strategies may help revive some hastily discontinued
drugs and could also reduce the cost of new drugs
entering the cancer pipeline.
But are we there yet? Not quite; however, it is pre-
dicted that within the next 10 years, newer technologi-
cal advances plus methodologies better developed to
make ana­lysis software economical, easy-to-use and
References 7 Schadt EE, Friend SH, Shaywitz DA.
1 Swinney DC, Anthony J. How were new
medicines discovered? Nat. Rev. Drug. Discov.
10(7), 507–519 (2011).
8 von Eichborn J, Murgueitio MS, Dunkel M,
2 Pache RA, Aloy P. A novel framework for the
comparative ana­lysis of biological networks.
PLoS ONE 7(2), e31220 (2012).
3 Larhlimi A, Blachon S, Selbig J, Nikoloski
Z. Robustness of metabolic networks: a
9 Barabasi AL, Gulbahce N, Loscalzo
review of existing definitions. Biosystems
106(1), 1–8 (2011).
4 Gerlinger M, Rowan AJ, Horswell S et al.
Intratumor heterogeneity and branched
10 Wist AD, Berger SI, Iyengar R. Systems
evolution revealed by multiregion
sequencing. N. Engl J. Med. 366(10),
883–892 (2012).
11 Pujol A, Mosca R, Farres J, Aloy P. Unveiling
5 Peters JU, Hert J, Bissantz C et al. Can we
discover pharmacological promiscuity early in
the drug discovery process? Drug Discov.
Today 17(17–18), 325–335 (2012).
12 Zhao S, Iyengar R. Systems pharmacology:
6 Anderson AR, Quaranta V. Integrative
mathematical oncology. Nat. Rev. Cancer
8(3), 227–234 (2008).
future science group
| Editorial
more acceptable to molecular biologists and pharma-
ceutical researchers will no doubt result in the use of
network analyses as a priority tool in drug develop-
ment. In conclusion, network pharmacology certainly
has the potential to change our view of drug design
and understanding mechanisms of action and, if used
correctly, is predicted to significantly de-risk cancer
drug discovery.
Acknowledgements
The author wishes to give sincere thanks to FWJ Beck for proof
reading this article. This editorial is an overview of the theme dis-
cussed at the Molecular Medicine Tricon Conference 2012, Drug
Discovery and Development Channel, De-risking Drug Discovery.
A substantial proportion of the content of this article is taken ver-
batim from the course materials prepared by Dr A V Whitmore,
Dr J Wray and Professor M P Young of e-Therapeutics PLC and
their contribution is gratefully acknowledged.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement
with any organization or entity with a financial interest in or finan-
cial conflict with the subject matter or materials discussed in the
manuscript. This includes employment, consultancies, honoraria,
stock ownership or options, expert t­estimony, grants or patents
received or pending, or royalties.
No writing assistance was utilized in the production of this
manuscript.
Pharmacol. Toxicol. 52, 505–521 (2012).
A network view of disease and compound 13 Azmi AS, Wang Z, Philip PA, Mohammad
screening. Nat. Rev. Drug Discov. 8(4), RM, Sarkar FH. Proof of concept: network
286–295 (2009). and systems biology approaches aid in the
discovery of potent anticancer drug
Koerner S, Bourne PE, Preissner R. combinations. Mol. Cancer Ther. 9(12),
PROMISCUOUS: a database for network- 3137–3144 (2010).
based drug-repositioning. Nucleic Acids Res. 14 Cokol M, Chua HN, Tasan M et al.
39, D1060–D1066 (2011). Systematic exploration of synergistic drug
pairs. Mol. Syst. Biol. 7, 544 (2011).
J. Network medicine: a network-based 15 Xie L, Evangelidis T, Xie L, Bourne PE. Drug
approach to human disease. Nat. Rev. Genet. discovery using chemical systems biology:
12(1), 56–68 (2011). weak inhibition of multiple kinases may
contribute to the anti-cancer effect of
pharmacology and genome medicine: a future nelfinavir. PLoS Comput. Biol. 7(4), e1002037
perspective. Genome Med. 1(1), 11 (2009). (2011).
16 Young MP, Zimmer S, Whitmore AV. Drug
the role of network and systems biology in molecules and biology: network and systems
drug discovery. Trends Pharmacol. Sci. 31(3), aspects. In: Designing Multi-target Drugs, RSC
115–123 (2009). Drug Discovery Series 21. Morphy JR, Harris
CJ (Eds). Royal Soc. Chem. 32–49 (2012).
network ana­lysis to identify multiscale
mechanisms of drug action. Annu. Rev.
www.future-science.com 941