expert reviews

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Promiscuous drugs as therapeutics for chemokine receptors

Promiscuous drugs as therapeutics
for chemokine receptors
Richard Horuk
Chemokine receptor antagonists that held much promise for the treatment of
autoimmune and inflammatory diseases have recently performed poorly in
clinical trials, resulting in disappointment for both pharmaceutical companies
and patients. This review focuses on the redundancy of the molecular target
as one potential reason for the failure of some of these antagonists to fulfil
their initial promise, and discusses the use of drugs that are capable of
interacting with more than one drug target – so-called promiscuous drugs –
as possible approaches to overcome this difficulty. Several clinically approved
promiscuous drugs, such as aspirin and olanzapine, are already used
successfully. This review discusses examples of promiscuous drugs for
G-protein-coupled receptors, including progress in developing dual-specific
chemokine receptor antagonists, and considers evidence for the possible
therapeutic utility of such drugs.
Autoimmune and inflammatory diseases – disease (Refs 14, 15), asthma (Refs 16, 17),
including diabetes, multiple sclerosis, cardiovascular disease (Refs 18, 19), transplant
rheumatoid arthritis and asthma – affect rejection (Refs 20, 21), cancer (Refs 22, 23) and
millions of individuals each year and place a acquired immune deficiency syndrome (AIDS).
huge health burden on our society. (Refs 24, 25) (Fig. 1). Chemokine receptors
Pharmaceutical companies have poured billions belong to the rhodopsin family of G-protein-
of dollars into research and development to try coupled receptors (GPCRs) (Ref. 26). More than
to identify safe and effective drugs to treat 40% of all marketed therapeutics act on GPCRs
these diseases. A major focus of interest for (Ref. 27) and they figure prominently in the lists
pharmaceutical companies has been inhibition of top-selling prescription drugs (Ref. 28).
of chemokine receptors (Ref. 1). Chemokines, The cost of bringing a new drug to market is
working through their cell-surface receptors more than US$800 million (Ref. 29). This high
to induce chemotaxis, are involved in expense can be partly attributed to the fact that
orchestrating the immune response and they for every successful marketed drug that a
play a central role in host defence (Ref. 2); company produces, thousands of others in
however, inappropriate activation of this research and development fail (Ref. 30). Drugs
network has been implicated in the in development can fail for several reasons,
pathogenesis of a number of diseases including including general toxicity, poor drug-like
diabetes (Refs 3, 4), rheumatoid arthritis (Refs 5, properties or limited clinical efficacy, but a
6), multiple sclerosis (Refs 7, 8, 9, 10, 11), recent analysis suggests that the latter accounts
psoriasis (Refs 12, 13), inflammatory bowel for greater than 40% of failures in the clinic

Department of Pharmacy, Touro University, 1310 Johnson Lane, Vallejo, CA 94592, USA. Tel: +1 925
708 0358; E-mail: horuk@pacbell.net

1
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Promiscuous drugs as therapeutics for chemokine receptors

Diabetes Arthritis
CCR1, 2. 4. 5 CCR1, 2, 5
CXCR3 CXCR2, 3
Multiple CX3CR1 CX3CR1 Cardiovascular
sclerosis disease
CCR1, 2, 5 CCR1, 2, 5
CXCR3 CXCR3
CX3CR1

Psoriasis Chemokine receptor Asthma

CCR2, 4, 8 signalling in CCR2, 3, 4, 5
CXCR2, 3 pathophysiology CXCR3

Inflammatory AIDS
bowel disease CCR5
CCR2, 4, 5. 9 CXCR4
CXCR2, 3 Transplant Cancer
CX3CR1 rejection CCR10
CCR1, 2, 5 CXCR4
CXCR3 CX3CR1

Chemokine receptors with a potential role in disease pathogenesis

Expert Reviews in Molecular Medicine © 2009 Cambridge University Press

Figure 1. Chemokine receptors with a potential role in disease pathogenesis. Chemokine receptors that
have been identified as playing a potential role in the pathogenesis of specific diseases are indicated (for
selected references see the first paragraph of the main text). The receptors are classified according to the
chemokines that they bind: CXC chemokines have a single amino acid between their invariant N-terminal
cysteines; in the CC class the first two cysteines are adjacent; CX3C chemokines have three amino acids
separating the N-terminal residues; and the final C class has only a single cysteine.

(Ref. 30). Limited clinical efficacy can be ascribed receptor CCR1 and failed to demonstrate any
to a variety of possible causes, but this review efficacy in a Phase II trial for multiple sclerosis
focuses on just one of these: the inherent (Ref. 31). Multiple sclerosis is an extremely
redundancy of the molecular target in the heterogeneous disease (Ref. 36) and several
human disease as a potential problem in drug chemokines and their receptors have been
discovery. This is illustrated with reference to reported to play a role in driving the
the recent spate of failures of chemokine pathophysiology (Fig. 1). Thus, depending on
receptor antagonists in the clinic. the expression and activation of these receptors
A number of chemokine receptor antagonist in patients with multiple sclerosis, more than
programmes have been terminated in clinical one chemokine receptor may have to be
trials (Table 1), and several of these antagonists inhibited for an antagonist to show efficacy in a
failed in Phase II clinical studies because they clinical trial.
did not meet their clinical endpoints (Refs 31,
32, 33, 34, 35). Each of these trials involved Polypharmacology
small-molecule antagonists that blocked only Indeed, for the treatment of complex
one chemokine receptor. For example the multifactorial diseases it has been suggested
antagonist BX 471, developed by Schering AG that so-called promiscuous compounds, which
(Berlex), was specific for the chemokine target more than one receptor or enzyme, might
2
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 Table 1. Failed clinical trials reported for chemokine receptor antagonists

Receptor Company Clinical Compound Indication Status

target Phase
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CCR1 Schering AG II BX 471 Multiple sclerosis, No efficacy in three separate Phase II trials;
(Berlex) psoriasis, endometriosis development halted

Millennium II MLN 3701 Rheumatoid arthritis No efficacy for rheumatoid arthritis

https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1462399409000921
MLN 3897 Multiple sclerosis Multiple sclerosis trial not reported

Pfizer II CP-481,715 Rheumatoid arthritis No efficacy; trials halted

CCR2 Merck II MK-0812 Rheumatoid arthritis, No efficacy in rheumatoid arthritis; multiple

multiple sclerosis sclerosis trial not reported; development halted

CXCR3 Amgen II T487 Psoriasis No efficacy; trial halted

CCR3 GlaxoSmithKline I 766994 Asthma, allergic rhinitis No longer reported

Bristol-Myers I DPC-168 Asthma No longer reported

Squibb
CCR5 Schering Plough III Vicriviroc HIV infection Toxicity; development uncertain

GlaxoSmithKline III Aplaviroc HIV infection Toxicity; development halted

Abbreviations: HIV, human immunodeficiency virus. For an explanation of chemokine receptor nomenclature, see Figure 1 legend.

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Promiscuous drugs as therapeutics for chemokine receptors

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be more effective therapeutics than specific drugs
that block a single target (Refs 37, 38). This new
paradigm has been called polypharmacology
(Ref. 39).
Numerous examples of clinically accepted
promiscuous drugs exist, of which aspirin is
the most classically cited. Aspirin is effective
therapeutically in a variety of situations,
including as an anti-inflammatory agent
(reducing fever, and aches and pains) and in
cardiovascular medicine, where it has platelet-
thinning effects and given chronically is useful
in preventing heart attacks (Ref. 40) It is well
known that these beneficial effects of aspirin
probably derive at least in part from its inhibition
of specific cyclooxygenase (COX1 and 2)
pathways, which lead to the inhibition
of prostaglandin and thromboxane synthesis
(Ref. 41). However, the anti-inflammatory effects
of aspirin could also be due to its ability to
generate novel anti-inflammatory mediators
known as aspirin-triggered 15-epilipoxins (Ref. 42).
Combination therapies (cocktails of several
drugs taken together that target different
proteins) are already used to treat cancer and
AIDS, since no single drug alone would be
effective in treating these complex diseases. For
the treatment of AIDS for example, cocktails of
several reverse transcriptase inhibitors, protease
inhibitors and fusion inhibitors are given
(Ref. 43). The disadvantage of combination
therapies is that each drug that is part of the
combination has to go through safety testing
and optimisation for ADME (‘absorption,
distribution, metabolism and excretion’) prior
to testing in the clinic. Thus, this would
increase drug development costs and time
taken for drug approval. In this context,
perhaps a single drug that hits multiple targets
might be more effective in the treatment of
complex autoimmune diseases. The advantages
and disadvantages of promiscuous drugs that
target more than one receptor are reviewed
below, together with examples of dual-specific
chemokine receptor antagonists.
Successful receptor-promiscuous drugs
To anyone familiar with screening nonpeptide
drug libraries to identify molecules specific for
a particular GPCR, the concept of receptor-
promiscuous drugs is certainly not new. In fact,
all too often drugs that target multiple receptors
are discovered from such screening campaigns.
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Promiscuous drugs as therapeutics for chemokine receptors
Although this is not usually desirable because
of off-target effects, it can in some cases be
beneficial therapeutically. The use of receptor-
promiscuous drugs has made an impact
in treating very complex diseases like
schizophrenia, mood disorders and cancer
(Ref. 38); such diseases involve a variety of
molecular mechanisms and respond well to a
multitarget approach. Two examples, discussed
below, serve to illustrate the success of this
approach.
The first example is the antipsychotic drug
olanzapine (Zyprexa, Eli Lilly), with sales
in 2002 alone of US$4 billion. Importantly,
this tricyclic benzodiazepine binds with high
affinity to more than a dozen GPCRs from
separate families (Ref. 44). Its promiscuity is
important for its activity since attempts made to
tailor the drug to be more specific result in a
loss of potency without reducing its side effects
(Ref. 38). In this case, the ability of the drug
to block serotonergic and dopaminergic
receptors is probably an advantage, as it is
thought that both receptors play a role in
schizophrenia (Ref. 38). One caveat with
promiscuous compounds is potential off-target
actions; for example, olanzapine effectively
targets the histamine receptor H1 and this has
undesirable side effects such as weight gain
(Ref. 45).
The second example is the cancer drug sutent
marketed by Pfizer to treat mainly kidney and
gastrointestinal cancers (Ref. 46). Sutent has
been shown to inhibit multiple receptor
tyrosine kinases, including the platelet-derived
growth factor (PDGF) receptor, vascular
endothelial growth factor (VEGF) receptor, KIT
and FLT3 (Ref. 46). In a recent report, the
contribution of each of these receptor kinases in
promoting tumour growth was examined
individually with specific receptor kinase
inhibitors. These studies showed that the
promiscuous drug sutent was more efficient in
inhibiting tumour growth than was blocking
single receptor kinases with specific inhibitors,
thus suggesting that its beneficial therapeutic
effects derived mainly from its ability to target
and inhibit multiple receptor kinases (Ref. 47).
Sutent is a positive example of a promiscuous
drug that is therapeutically very effective – in
inducing remission and long-term survival in
patients with kidney and gastrointestinal cancer
(Ref. 48).
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Based on the examples above, it is obvious that
small-molecule drugs can bind to multiple
proteins. If this receptor promiscuity could be
suitably harnessed in the design of dual
inhibitors of GPCRs, it could be a useful
approach in treating several diseases. For
example, the design of dual inhibitors that
could target both of the chemokine – HIV
coreceptors – CXCR4 and CCR5 – would lead
to very powerful therapeutics to treat AIDS.
Similarly, antagonists that could inhibit the
sphingosine 1-phosphate receptor 1 (S1P1) and
the chemokine receptor CCR2 might be very
effective antiatherogenic agents, given the
beneficial effects of S1P1 modulators and
CCR2 gene deletion in animal models of
atherosclerosis (Refs 49, 50). Although the idea
is attractive, the probability of discovering dual-
GPCR inhibitors might at first be considered
highly unlikely given the huge diversity in the
range of ligands that act on GPCRs, and it
might be expected that the success of this
approach would rely entirely on the similarity
of the receptor binding pockets of the GPCRs in
question. In fact, as shown by the examples
below, this is not the case. The rationale for
discovering promiscuous nonpeptide ligands
utilises a variety of approaches and ideas, and
this review merely skims the surface; for a more
exhaustive treatment see the excellent reviews
on this topic provided by Refs 38 and 51.
Dual GPCR antagonists by design
AT1 –ETA antagonist
A classic example of a strategy to design dual
GPCR inhibitors is that taken to discover potent
antagonists for the type 1 angiotensin II
receptor (AT1) and the type A endothelin
receptor (ETA). The ligands for these receptors –
angiotensin II and endothelin – are potent
vasoconstrictors, and dual antagonists of these
two receptors should be of greater benefit in
the treatment of pulmonary hypertension,
congestive heart failure and arteriosclerosis.
Although the overall sequence identity of AT1
and ETA is low (only 19%), it has proven
possible to design antagonists that bind both
receptors with high affinity (Ki in the low
nanomolar range). This work originated from
the observation that biphenylsulphonamides
were highly potent and selective ETA
antagonists (Fig. 2b) and bore a structural
similarity to the biphenyltetrazole structures
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Promiscuous drugs as therapeutics for chemokine receptors
that are often found in AT1 antagonists (Fig. 2a).
By merging together some of the key structural
elements present in an AT1 antagonist with
those of a biphenylsulphonamide ETA
antagonist, a scaffold was provided that had
potent antagonist activity against both receptors
(Refs 52, 53) (Fig. 2c). Losartan (an AT1
antagonist) and SB-290670 (a dual ETA – ETB
antagonist) each decreases blood pressure in a
spontaneously hypertensive rat model of
hypertension (Ref. 54). As might be expected,
combinations of these antagonists given
together are additive in decreasing blood
pressure (Ref. 54). In line with these data, a
dual AT1 – ETA antagonist was shown to be
more efficacious than an AT1 blocker at
lowering blood pressure in spontaneous
hypertensive rats (Ref. 54). We may soon learn
whether such dual antagonists will be clinically
useful since the pharmaceutical company
Pharmacopeia has licensed a dual AT1 – ETA
antagonist (PS433540) from Bristol-Myers
Squibb and announced through a press release
that its Phase IIa clinical trial with the
compound yielded positive efficacy and safety
results in patients with stage 1 and stage 2
hypertension (http://www.pharmacopeia.com/
wt/page/press/pr_1210796712).
H1 – TxA2 antagonist
Histamine and thromboxane play an important
role in the pathogenesis of asthma, and thus
dual inhibitors of their receptors might provide
potent anti-inflammatory compounds to treat
this disease. The development of dual
antagonists for the histamine receptor H1 and
the thromboxane A2 receptor (TxA2) (Ref. 55)
was based on the observation that compounds
discovered to be potent antagonists to both
of these receptors contained a common
benzoxepin core (Fig. 2d and e). Judicious
replacement of the benzimidazole group,
crucial for the TxA2 receptor antagonist activity
(Fig. 2e), with a tertiary amine (Fig. 2f) resulted
in a dual antagonist that was active at both of
these receptors.
Clearly this approach, and the one just
discussed above, worked well because highly
potent templates to both receptors that had
common core structures existed and these were
tractable enough to allow a hybrid molecule
that could interact with the binding pockets of
both receptors to be designed. These examples
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Promiscuous drugs as therapeutics for chemokine receptors

H3C N
H3C N
O N N
N
O
O

H3C O
N O N
N O
N O O
O O CH3 S CH3
N S
N N
N H
H H CH3
CH3

a AT1 antagonist b ETA antagonist c Dual AT1 and ETA antagonist

AT1 Ki = 0.8 nM AT1 Ki = >10 000 nM AT1 Ki = 0.8 nM
ETA Ki = >10 000 nM ETA Ki = 1.4 nM ETA Ki = 9.3 nM

N N N

HO HO HO

O O O
O O O

d H1 antagonist e TxA2 antagonist f Dual H1 and TxA2 antagonist

TxA2 Ki = >1000 nM TxA2 Ki = >15 nM TxA2 Ki = 740 nM
H1 Ki = 11 nM H1 Ki = 20 nM

OH OH O
H
OH OH O N
HO
OH

g BLT1 agonist LTB4 ethanolamide

LTB4 TRPV1 agonist
h BLT1 antagonist
S TRPV1 agonist
F
N N
H H

i Dual BLT1 and NHSO2Me

TRPV1 antagonist
OH O3367

The design of promiscuous GPCR antagonists

Expert Reviews in Molecular Medicine © 2009 Cambridge University Press

Figure 2. The design of promiscuous GPCR antagonists. (See next page for legend.)
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Promiscuous drugs as therapeutics for chemokine receptors

Figure 2. The design of promiscuous GPCR antagonists. (Legend; see previous page for figure.) (a –c) The
design of dual antagonists for the angiotensin II receptor (AT1) and the type A endothelin receptor (ETA). This
approach is based on the idea that a phenylsulphonamide core is a central component of a class of potent
and selective ETA antagonists (b). The biphenyl core of these compounds has a structural similarity to the
biphenyltetrazole core of AT1 antagonists, including irbesartan (a). These observations allowed the design of
potent AT1 and ETA dual receptor antagonists (e.g. c). The ETA antagonist core is shown in red; the AT1
antagonist scaffold is shown in blue. (d–f) The design of dual anatagonists for the receptor for thromboxane
A2 (TxA2) and the histamine receptor H1. The rationale for the design of antagonists to these two receptors is
based on the idea that they contain a common benzoxepin core, shown in blue. (g–i). The design of leukotriene
B4 receptor (BLT1) and vanilloid receptor (TRPV1) dual antagonists. This approach is based on the idea that
LTB4 (and other lipoxygenase metabolites of anandamide) can activate TRPV1 and BLT1. Since similar
structures can activate very different receptors, it was reasoned that the design of a single antagonist that
inhibits them both might prove to be feasible. For O3367, BLT1 antagonist Ki ¼ 60 nM (inhibition of LTB4-induced
chemotaxis); TRPV1 antagonist Ki ¼ 1100 nM (inhibition of capsicin-induced Ca2þ flux).

suggest that promiscuous antagonists can be
discovered for receptors that do not even share
a similar binding domain.
BLT1 –TRPV1 antagonist
A recent study described the design of potent
antagonists that were dual inhibitors of both the
leukotriene B4 (LTB4) receptor BLT1 (a GPCR
activated by LTB4) and the vanilloid receptor
TRPV1 (a ligand-gated, nonselective cation
channel) (Ref. 56). The premise for the design
of these dual antagonists arose from the
observation that LTB4 (and other lipoxygenase
metabolites of anandamide) can activate TRPV1
and BLT1 (Ref. 56). Since both of these receptors
play an important role in inflammation, it was
reasoned that the design of a single antagonist
that inhibits them both should be very useful
therapeutically. The rationale for designing the
dual antagonist came from the observation that
LTB4 ethanolamide (Fig. 2 h) had antagonist
properties on BLT1 and agonist properties on
TRPV1. These results led to the synthesis of
pharmacophores that were structurally similar
and proved to be interesting compounds that
could be good starting points to design more
highly potent antagonists of both receptors
(Ref. 56) (Fig. 2i). In this case, the two receptors
targeted by the antagonist belong to two very
different classes and are not likely to share
similar active sites.
Serendipitously discovered dual
GPCR antagonists
Dual antagonists can also be discovered
serendipitously, as recently described for a dual
antagonist of the chemokine receptor CCR3 and
the histamine receptor H1 (Ref. 57). These
receptors both play an important role in atopic
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diseases such as asthma and atopic dermatitis.
CCR3 is activated by the chemokines CCL11,
CCL24 and CCL26, which are upregulated in the
allergic response, regulating the recruitment of
eosinophils from the blood into tissues such as
the lung where they mediate inflammation. By
contrast, H1 is activated by the biogenic amine
histamine, which is one of the primary mediators
of the type 1 hypersensitivity response; it
induces vasodilation, bronchoconstriction and
smooth muscle cell activation, culminating in an
allergic response. Inhibitors of H1 have found
use clinically in the treatment of hay fever and
allergies, but have not been very effective in
treating asthma (Ref. 58).
Thus, the antagonism of this receptor pair by a
single drug might prove to be a more effective
therapeutic to treat T helper 2 (Th2)-like
inflammatory diseases such as asthma.
Interestingly, these two receptors have limited
homology (less than 14%) and are activated by
totally unrelated ligands (a protein and a
biogenic amine), yet are both potently inhibited
by a single nonpeptide, YM-344484 (Fig. 3).
This compound inhibits both the CCL11-
induced Ca2þ influx in human CCR3-expressing
cells (Ki ¼ 1.8 nM) and histamine-induced Ca2þ
influx in H1-expressing PC3 cells (Ki ¼ 47 nM)
(Ref. 57). This example serves to reinforce the
idea that it is not even necessary for the target
proteins of a promiscuous drug to have
identical binding sites, since it is quite likely
that YM-344484 inhibits CCR3 by allosteric
inhibition, as do most chemokine receptor
antagonists (Ref. 59). Furthermore, it also
illustrates the point that it is possible to obtain
dual antagonists even for GPCRs that have
highly dissimilar ligands. These dual H1 – CCR3
antagonists, and others like them identified in
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Promiscuous drugs as therapeutics for chemokine receptors

OH
OH
P
O O

O HO
H2N
N
N N O N

N F
H
a YM344484 b Phospho-FTY720
H1 Ki = 47 nM S1P1 EC50 = 1.3 nM
CCR3 Ki = 1.8 nM S1P3 EC50 = 2 nM
S1P4 EC50 = 41 nM
S1P5 EC50 = 40 nM
Structures and activities of nonpeptide promiscuous modulators of GPCRs
Expert Reviews in Molecular Medicine © 2009 Cambridge University Press

Figure 3. Structures and activities of nonpeptide promiscuous modulators of GPCRs. (a) YM344484 is a
potent antagonist for the histamine receptor H1 and the chemokine receptor CCR3 (Ref. 57). The discovery of this
compound demonstrates that it is possible to find dual antagonists for receptors that have totally different ligands
and presumably different binding pockets. (b) FTY720 is a sphingosine 1-phosphate receptor agonist. Although
not specifically developed to act on multiple sphingosine 1-phosphate receptors, phosphorylated FTY720
potently binds to four out of the five S1P receptors (Refs 61, 92).

the near future, should open up new therapeutic
opportunities for the treatment of allergic disease,
perhaps offering alternatives to current standard
therapies that employ high levels of steroids
(Ref. 60), with their associated drawbacks.
A cautionary note should be added here about
problems that could arise in developing
promiscuous GPCR drugs. FTY720, which is
endogenously converted in vivo to the active
metabolite phospho-FTY720 (Fig. 3), has found
clinical use in transplantation medicine and in
the treatment of multiple sclerosis. Currently
FTY720 is in Phase III clinical trials for multiple
sclerosis based on very positive Phase II data.
Although not originally developed as a
promiscuous drug, recent studies show that
FTY720 is, as the phosphorylated form, a potent
promiscuous agonist at four of the five S1P
receptors (Ref. 61). It is likely, but not known
for certain, that the beneficial effects of FTY720
derive from its potent promiscuous effects.
Unfortunately, however, the action of FTY720
on the receptor S1P3 induces unwanted
cardiovascular effects that include bradycardia,
and thus a narrower-spectrum S1P receptor
agonist might be more desirable for clinical
development. Based on this example it needs to
be borne in mind that receptor-promiscuous
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drugs do carry the danger of potentially
deleterious off-target effects on other proteins
or GPCRs.
Promiscuous chemokine receptor
antagonists
GPCRs bind a diverse array of ligands, including
peptides, lipids, nucleotides, amino acids, fatty
acids, metals, light and odourants, all of which
can activate the receptor (Ref. 62). It is unlikely
that this activation is accomplished by
engagement of a single common binding site,
although this has been postulated for the class
A or rhodopsin receptors in the past (Ref. 63).
This wide range of ligands more than likely
binds to distinctly different receptor domains
and induces signalling by changing the
conformation of the GPCRs, which then triggers
the G-protein pathways. For example,
chemokines, which are proteins, trigger this
conformational change by binding mainly to
the extracellular loops of the receptor (Ref. 64).
By contrast, the biogenic amines bind to a
helical cavity that encompasses transmembrane
helices III, V, VI and VII for some ligands
(Ref. 65). Interestingly, nonpeptide antagonists
to the chemokine receptors are mainly allosteric
inhibitors and bind to the biogenic-amine-like
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domains of the receptor, probably altering the
conformational switch so that the chemokines
can no longer activate their receptors (Refs 59, 66).
Since the examples discussed above suggest it is
possible to discover antagonists that will block
totally unrelated receptors, it should be feasible
to generate dual antagonists for chemokine
receptors. In fact, there are already parallels for
this in the cunning strategies that infectious
organisms have come up with to circumvent
the immune response (Ref. 67). Chemokines
and their receptors play an important role in
host defence, and infectious agents such as
viruses and parasites have generated cellular
antagonists and/or binding proteins to block
the action of chemokines and their receptors
(Refs 68, 69). Interestingly, virtually all of these
natural antagonists of the chemokine system are
promiscuous, including tick saliva proteins
(Ref. 70), viral chemokine-binding proteins
(Refs 68, 69) and viral chemokines (Refs 68, 69).
Examples of dual chemokine receptor
antagonists
The design of promiscuous chemokine receptor
antagonists should be aided by the number of
dual antagonists that have already been
described in the literature (Fig. 4). These are
mostly to the highly related receptors CCR1
and CCR3, which share around 59% sequence
identity (Refs 71, 72), or to CCR2 and CCR5,
which share around 72% sequence identity. A 2-
(benzothiazolylthio)acetamide compound from
Takeda (Fig. 4b) binds to both CCR1 and CCR3
with high affinity, displacing CCL3 with an IC50
of 450 nM for CCR1, and CCL11 with an IC50 of
32 nM for CCR3 (Ref. 73). Similarly, the
antagonist UCB 35625 (Fig. 4a) is a potent
antagonist for both receptors, inhibiting CCL3-
mediated chemotaxis by cells expressing CCR1
with an IC50 of 9.6 nM, and CCL11-mediated
chemotaxis by cells expressing CCR3 with an
IC50 of 93.7 nM (Ref. 74). For CCR2 and CCR5,
the two compounds TAK 779 and TAK 652
(both from Takeda; Fig. 4c and d) are potent
inhibitors of this receptor pair (Refs 75, 76).
Recently, Novartis reported at a meeting that
it was pursuing dual CCR2 – CCR5 inhibitors
(Ref. 77). Lead optimisation was based on a
highly lipophilic benzothiophene identified
from a high-throughput screen to yield a third-
generation 4-substituted indole series (e.g.
Fig 4e). This compound had high potency on
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expert reviews
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Promiscuous drugs as therapeutics for chemokine receptors
human and rodent CCR2 and CCR5, no toxicity
and good pharmacokinetic properties. The
compound was efficacious in an in vivo
peritoneal monocyte migration assay in the rat
and in a mouse colitis model, as well as in an
acute mouse experimental autoimmune
encephalomyelitis model of multiple sclerosis.
The challenge to medicinal chemists will be to
design dual-receptor antagonists that are effective
in targeting totally unrelated receptors such as
CCR5 and CXCR4 to generate drugs that would
be very effective as antiretroviral agents in
treating patients with AIDS. An obvious
question arising from such an approach is
whether it is possible to generate dual
antagonists that are able to accommodate the
receptor binding cavities of such different
chemokine receptors as those of the CC and
CXC classes. The answer to this may be yes,
given the recent disclosure of a dual CXCR2 –
CCR2 receptor antagonist (Ref. 78): although
CXCR2 and CCR2 belong to two different
chemokine receptor classes and have less than
20% sequence homology, a series of
thiazolo[4,5-d]pyrimidines were found to be
potent dual chemokine receptor antagonists.
One of these compounds, 30a, inhibited calcium
transients in cells expressing CXCR2 and CCR2
with IC50s of 1 nM and 8 nM, respectively.
Will dual chemokine receptor antagonists
be therapeutically effective?
With the exception of the CCR5 antagonist, which
is a registered antiretroviral agent, chemokine
receptor antagonists have not lived up to their
therapeutic promise (Refs 1, 79, 80). Chemokine
receptor redundancy has been proposed as one
reason, among many, to account for these
failures. The approach of simply targeting one
receptor may not be enough. Given the absence
of good clinical markers of disease, there is not
always a simple way to stratify patients in
clinical trials into appropriate groups that will
respond to treatment (i.e. groups showing
activation of a particular receptor pathway).
In the absence of such clinical markers,
promiscuous receptor drugs have been
proposed here as one possible approach to
target complex heterogeneous diseases like
multiple sclerosis. In support of this idea,
examples of successful promiscuous drugs like
olanzapine have been discussed, and evidence
has been presented that shows it is possible to
9
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Promiscuous drugs as therapeutics for chemokine receptors

Cl
O N

N S
N Cl
I– H
S b TAK 1e
N+
CCR1 IC50 = 450 nM
CCR3 IC50= 32 nM
NH Cl
O

H
N
O CH3 Cl–
Cl

H3C O N+ O
c TAK 779 CH3
a UCB 35625
CCR2 IC50 = 27 nM
CCR1 IC50 = 9.6 nM CCR5 IC50 = 1 nM
CCR3 IC50= 93.7 nM

i-Bu
d TAK 652
N
CCR2 IC50 = 5.9 nM
CCR5 IC50 = 3.1 nM
H
N
OBu Pr
O
N
S
O R2
N
N
O N R2

R1 O
N e Novartis Cpd 9
H
NH CCR2 IC50 = 1 nM
CCR5 IC50 = 0.8 nM

Structures of nonpeptide dual agonists of chemokine receptors

Expert Reviews in Molecular Medicine © 2009 Cambridge University Press

Figure 4. Structures of nonpeptide dual agonists of chemokine receptors. (a, b) UCB 35625 (Ref. 74) and TAK
1e (Ref. 73) are dual CCR1 and CCR3 antagonists. (c– e) TAK 779 (Ref. 75), TAK 652 (Ref. 76) and Novartis
compound (Cpd) 9 (Ref. 77) are potent dual CCR2 –CCR5 inhibitors. These antagonists demonstrate that it
is possible to generate small molecule inhibitors that act on more than one chemokine receptor.

generate dual-receptor antagonists of GPCRs, targeting more than one receptor is beneficial?
including chemokine receptors. Furthermore, The evidence for this is scant and summarised
promiscuous drugs that target receptors with below.
very different binding pockets and with very It is well established that chemokines play a
little homology to each other can clearly be role in atherogenesis; however, inhibition of
generated. Given that it is possible to come individual chemokines or chemokine receptors
up with promiscuous chemokine receptor has had only limited effects in animal models of
antagonists, what evidence is there that disease, suggesting that blocking multiple
10
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receptors might be required for efficacy. In line
with this, two recent reports show that blocking
multiple chemokines and/or chemokine
receptors is extremely effective in treating
atherosclerosis (Refs 19, 81). In the first study,
combined inhibition of CCL2 (a CCR2 ligand),
CX3CR1 and CCR5 in a hypercholesterolaemic,
atherosclerosis-susceptible apolipoprotein E antibodies to CXCR3 (Ref. 20). Recipient mice
(ApoE)-deficient mouse model of atherosclerosis
led to a reduction in circulating monocytes
despite a persistent hypercholesterolaemia
(Ref. 19). These effects were associated with an
almost complete reduction in atherosclerosis. In
the second study (Ref. 81), the authors reported a
four-arm atherosclerosis study in CX3CL1 (the
ligand for CX3CR1), CCR2 and ApoE triple-
knockout mice. The triple-knockout mice showed
a marked reduction in macrophage accumulation
in the artery wall together with a gross reduction
in the development of atherosclerosis. The overall
conclusion from these two studies is that
blocking multiple chemokine receptors is much
more effective in animal models of atherosclerosis
than blocking a single receptor, and it
underscores the potential benefit of promiscuous
chemokine receptor antagonists as useful
therapeutics.
A model of intimal hyperplasia in response
to femoral arterial injury was examined in
transgenic mice that were induced to express
M3 (Ref. 82), a herpes virus protein that binds
and inhibits multiple chemokines of all classes
including CC, CXC, C and CX(3)C (Ref. 83).
Induction of M3 expression resulted in a 67%
reduction in intimal area and a 68% reduction
in intimal:medial ratio after femoral artery
injury. By contrast to these data, targeted
deletion of a single chemokine, CCL2, in an
identical model resulted in only a 29%
reduction in intimal hyperplasia (Ref. 84),
suggesting that multiple chemokines and
receptors are involved in the pathophysiology.
Thus, these data underscore the therapeutic
utility of pan-specific chemokine blockade and
suggest that blocking more than one chemokine
can be therapeutically advantageous, at least in
this animal model.
The benefits of blocking two totally unrelated
chemokine receptors – CCR5 and CXCR3 –
both of which are important proinflammatory
receptors in autoimmunity, were recently
illustrated using knockout mice and receptor-
neutralising antibodies (Ref. 20). Both CCR5
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expert reviews
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Promiscuous drugs as therapeutics for chemokine receptors
and CXCR3 have previously been shown to
play a role in organ transplant rejection, mainly
by inducing infiltration of T cells into the
transplanted organs (Refs 85, 86). A heterotopic
heart transplantation model in BALB/c to B6/
129 mice deficient in CCR5 was carried out in
the absence and presence of neutralising
were then assessed daily for allograft function
by abdominal palpation, and graft survival was
confirmed by laparotomy. The donor hearts in
the CCR5-deficient control group were all
rejected at 6 days post-transplantation. The
survival of the donor hearts in the CCR5-
deficient mice receiving control antibody and
in the wild-type mice receiving anti-CXCR3
antibodies was prolonged to 29 and 34 days,
respectively. However, the animals receiving a
combined blockade of CXCR3 and CCR5 had a
greater than 15-fold prolonged allograft
survival compared with the control group; all
of the allografts survived for greater than 100
days, after which the study was terminated.
In addition, the donor hearts did not display
any of the signs that are characteristic of
chronic rejection. In summary, these studies
demonstrate that blocking the chemokine
receptors CCR5 and CXCR3 with dual
antagonists could be beneficial in acute organ
transplantation rejection.
Concluding remarks
It has been suggested here that chemokine
receptor redundancy could be, at least in part,
responsible for some of the recent clinical
failures in chemokine receptor antagonist
programmes. Demonstrating clinical efficacy
with a specific antagonist to a single receptor is
difficult because we do not yet possess the
ability to separate patients into chemokine-
receptor-specific subpopulations for a specific
disease. This approach, sometimes called
personalised medicine, was elegantly pioneered
by Genentech to identify and treat the
subpopulation of HER2-expressing breast
cancer patients with trastuzumab (Herceptin),
an antibody to HER2 (Ref. 87). About 25% of
breast cancer patients overexpress the EGF
receptor family member HER2, and the same
antibody to the receptor that is used to treat
this cancer was initially used to identify this
subpopulation, making it easier to stratify
patient groups in clinical trials. Detection of
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HER2 overexpressers allowed smaller clinical
trials for a shorter duration, saving drug-
development money and allowing
demonstration of strong proof of efficacy. If we
had the ability to do this with chemokine
receptors, then perhaps single specific
antagonists would be more effective. In the
absence of such information, promiscuous
chemokine receptor antagonists, or indeed
combination therapies with several specific
antagonists, could perhaps overcome the
problem of receptor redundancy. This approach
should be more successful than previous ones,
and could provide ultimate benefit in treating
complex autoimmune diseases. With the
examples discussed here and the progress being
made in solving the three-dimensional structure
of GPCRs (Refs 88, 89, 90, 91),
polypharmacology applied to the chemokine
receptor field could, in the near future, be a
very interesting and novel way to generate
effective therapeutics.
Acknowledgements and funding
I thank the peer reviewers of this review for
helping to increase its clarity.
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Promiscuous drugs as therapeutics for chemokine receptors

Further reading, resources and contacts
Publications
Roth, B.L., Sheffler, D.J. and Kroeze, W.K. (2004) Magic shotguns versus magic bullets: selectively non-
selective drugs for mood disorders and schizophrenia. Nature Reviews Drug Discovery 3, 353-359
This article discusses the idea that promiscuous drugs (‘magic shotguns’) that interact with several molecular
targets might be more effective than specific drugs (‘magic bullets’) in treating complex multifactorial
diseases such as schizophrenia and depression.

Morphy, R., Kay, C. and Rankovic, Z. (2004) From magic bullets to designed multiple ligands. Drug Discovery
Today 9, 641-651
The authors discuss strategies for designing promiscuous drugs that target several proteins. The article has
interesting lists of drugs that hit several targets and is a good resource for those wishing to explore the topic
of promiscuous drugs in more detail.

Murphy, P.M. et al. (2000) International Union of Pharmacology. XXII. Nomenclature for chemokine receptors.
Pharmacological Reviews 52, 145-176
This is an excellent review on chemokine receptors that is as good starting point for those wishing to learn more
about this family of proteins. It discusses each cloned receptor in turn.

Websites
An excellent resource of databases and information on all things pertaining to G-protein-coupled receptors can
be found at:
http://www.gpcr.org/7tm/
A database of G-protein-coupled receptors maintained by the International Union of Pharmacology (IUPHAR)
gives detailed information for all GPCRs, including useful information on their ligands, agonists, antagonists
and selected publications:
http://www.iuphar-db.org/GPCR/ReceptorFamiliesForward
The DrugBank database is an excellent resource providing chemical, pharmacological and pharmaceutical
information for close to 4800 drugs of biological and clinical interest:
http://www.drugbank.ca

Features associated with this article

Figures
Figure 1. Chemokine receptors with a potential role in disease pathogenesis.
Figure 2. The design of promiscuous GPCR antagonists.
Figure 3. Structures and activities of nonpeptide promiscuous modulators of GPCRs.
Figure 4. Structures of nonpeptide dual agonists of chemokine receptors.
Table
Table 1. Failed clinical trials reported for chemokine receptor antagonists.

Citation details for this article

Richard Horuk (2009) Promiscuous drugs as therapeutics for chemokine receptors. Expert Rev. Mol. Med.
Vol. 11, e1, January 2009, doi:10.1017/S1462399409000921

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Accession information: doi:10.1017/S1462399409000921; Vol. 11; e1; January 2009
& 2009 Cambridge University Press
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