review

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Drug Insight: tumor necrosis factor-converting

enzyme as a pharmaceutical target
for rheumatoid arthritis
Marcia L Moss*, Liora Sklair-Tavron and Raphael Nudelman
S U M M ARY
The success of agents that inhibit tumor necrosis factor (TNF), such as
infliximab, adalimumab and etanercept, has led to a desire for orally
available small molecules that have a better safety profile and are less costly
to produce than current agents. One target for anti-TNF therapy that is
currently under investigation is TNF-converting enzyme, which promotes
the release of soluble TNF from its membrane-bound precursor. Inhibitors
of this enzyme with drug-like properties have been made and tested in the
clinic. These inhibitors include TMI-005 and BMS-561392, both of which
have entered into phase II clinical trials. This article summarizes preclinical
and clinical findings regarding the use of inhibitors of TNF-converting
enzyme for the treatment of rheumatoid arthritis.
keywords ADAM, clinical trial, rheumatoid arthritis, TACE, TNF

Review criteria
PubMed was searched in March 2007 for full papers and abstracts published
in English-language journals using the following keywords alone or in
combination: TNF, rheumatoid arthritis, review, meta-analysis in
humans, metalloproteinase, shedding, ADAM, disintegrin, BMS-561392,
TMI, GW3333, and GI5402. For the chemistry section, Chemical Abstracts
STN database, Adis R&D Insight and Pharmaprojects were searched using the
following terms: TACE and TNF-alpha converting enzyme or convertase
inhibitors. No early time limit was placed on any of the search criteria.

ML Moss is a Founder of BioZyme, Apex, NC, USA, and L Sklair-Tavron is

a Project Leader and R Nudelman is a Manager in the Medicinal Chemistry
Department at Teva Pharmaceutical Industries, Petah Tikva, Israel.
Correspondence
*BioZyme Inc., 1513 Old White Oak Church Road, Apex, NC 27523, USA
mmoss@biozyme-inc.com
Received 28 November 2007 Accepted 19 February 2008 Published online 15 April 2008
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doi:10.1038/ncprheum0797

300 nature clinical practice RHEUMATOLOGY

INTRODUCTION

The cytokine tumor necrosis factor (TNF) has

an important role in inflammatory processes in
rheumatoid arthritis (RA) and in other immunemediated disorders.1,2 Consequently, TNF has
emerged as an important target for the develop
ment of therapeutic strategies for treating RA
and Crohns disease. The TNF inhibitors that
have been approved for clinical use to treat RA
are infliximab, adalimumab and etanercept.
Infliximab is a chimeric mousehuman monoclonal antibody, whereas adalimumab is a fully
humanized monoclonal antibody; both agents
are specific for TNF. Etanercept is a fusion
protein comprising the ligand-binding portion
of the human p75 TNF receptor (TNFRII)
and the Fc fragment of human IgG1. The TNF
inhibitors cause their primary effect by blocking
the interaction of TNF with cell-surface
receptors (Figure 1).
The ultimate goals of RA treatments are the
prevention or control of joint damage and
the prevention of functional loss. Despite the
optimal use of other disease-modifying antirheumatic drugs (DMARDs)in particular,
methotrexatethe outcome for many patients
with RA includes severe functional decline and
considerable adverse effects. Thus, biologic
anti-TNF agents, often used in combination
with methotrexate, are now the first choice
of treatment when other DMARDs fail in
clinical practice.35
TNF antagonists, used alone or in combination with methotrexate, are superior to
methotrexate alone or placebo in improving
the signs and symptoms of RA, slowing radiographic progression of structural joint damage,
and reducing functional disability.68 Indirect
comparisons indicate that efficacy does not
differ substantially among biologic anti-TNF
drugs.5 Treatment with TNF antagonists early in
the course of disease has a considerably greater
benefit than treatment with previous standard
therapies, with a higher number of responders,
a higher degree of response and possible arrest
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of joint damage.9,10 Owing to financial consider

ations, however, it is often not possible to treat
patients at the earlier stages of the disease.
Efficacy trials have shown that anti-TNF drugs
have good tolerability profiles, but have recorded
rare but serious adverse events, such as infections
and lymphoma, that could not be assessed reliably.5,11 A meta-analysis that pooled data from
clinical trials of adalimumab and infliximab
reported that patients treated with anti-TNF
drugs experienced twice as many serious infections as did those taking placebo.11 Keane et al.
reported that the most common serious infection in patients treated with infliximab was
tuberculosis.12 There is insufficient evidence to
allow us to draw conclusions about an increased
risk of specific malignancies.13 Injection site
reactions (adalimumab and etanercept) and
infusion reactions (infliximab) were the most
commonly and consistently reported adverse
events in the meta-analysis.11 Some infusion
reactions seemed to be more serious than injection site reactions. Nevertheless, less than 2%
of patients discontinued anti-TNF therapy and
withdrew from the clinical trials because of
infusion reactions.
The benefit of anti-TNF drugs to patients is
considerable and might outweigh the risk of
infections, especially in cases of severe erosive
RA. Although the cost of therapy remains an
important problem, there is still an unmet
medical need for novel approaches (oral therapies) that carry higher clinical benefit, lower
cost and a lower risk of adverse events than
current treatments.
The focus of this Review is on small molecular
inhibitors of TNF-converting enzyme (TACE)
that slow the progression of RA by preventing
the release of soluble TNF from its membranebound precursor. The rationale for using TACE
inhibitors for the treatment of RA is discussed. In
addition, findings are reported from preclinical
and clinical tests of orally available compounds
that have improved the selectivity of such inhibitors for TACE over the closely related matrix
metalloproteinases (MMPs).
TACE AS A THERAPEUTIC TARGET
FOR Rheumatoid Arthritis

Inhibitors (rather than antagonists) that are orally

available and are considered as anti-TNF therapies fall into two main classes: those that prevent
the production of TNF and those that stop the
release of soluble TNF from immune-competent
june 2008 vol 4 no 6 MOSS ET AL. 

Cell membrane

TNFRI

TNFRII

sTNF

Etanercept

TACE
inhibitor

TACE

sTNF

Infliximab or
adalimumab

proTNF

TACE

Figure 1 Anti-TNF therapies and their effect on TNF signaling. Etanercept,

a fusion protein of TNFRII and the Fc region of IgG1, and the anti-TNF
antibodies infliximab and adalimumab, bind to TNF and prevent the molecule
from interacting with its two receptors, TNFRI and TNFRII, thereby stopping
signaling events. These large inhibitor molecules prevent binding of either
sTNF or proTNF to their membrane receptor targets. TACE processes proTNF
from the cell membrane to yield sTNF. Inhibitors of TACE block signaling by
the soluble, but not membrane-bound, form of TNF. Abbreviations: proTNF,
precursor TNF; sTNF, soluble TNF; TACE, TNF-converting enzyme; TNF, tumor
necrosis factor; TNFRI, TNF receptor I; TNFRII, TNF receptor II.

cells. TACE, the enzyme that processes precursor

TNF in order to release soluble TNF, is a member
of the ADAM (a disintegrin and metallo
proteinase) family and is known as ADAM17.14,15
TACE was purified on the basis of its capacity
to process precursor TNF, and cells taken from
TACE-deficient mice in which the zinc-binding
motif of TACE is mutated are unable to process
precursor TNF.14 TACE is also required for
epidermal growth factor signaling, as TACEdeficient mice have a phenotype similar to that
of mice that lack transforming growth factor
and of mice that lack epidermal growth factor
receptor.16 TACE-deficient mice exhibit open
eyes and wavy hair at birth, which is reminiscent
of the phenotype of transforming growth factor
knockout mice. Mice lacking TACE also show
epithelial defects in the lung bronchioli that are
similar to those in mice that lack the epidermal
growth factor receptor. Given the characteristics
of the TACE knockout phenotype, investigators
are actively seeking inhibitors of TACE that could
potentially treat cancer (Box 1). These inhibitors
might be more beneficial for the treatment of

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Box 1 TACE as a pharmaceutical target for

cancer and other conditions.
Tumor necrosis factor-converting enzyme (TACE)
inhibitors could potentially be used to treat
cancer. TACE can process many of the epidermal
growth factor receptor (EGFR) ligandssuch as
amphiregulin, epiregulin, epigen and transforming
growth factor (TGF-)16,3941that bind to
EGFR, a member of the ErbB tyrosine kinase
family of receptors. Ligand binding causes EGFR
dimerization, which activates the kinase domain.
Subsequent phosphorylation of the receptor
ultimately leads to cell proliferation. Lapatinib,
which prevents dimerization of the EGFR, has
been approved to treat breast cancer, indicating
the feasibility and efficacy of inhibiting EGFR
signaling.42 In addition, a TACE inhibitor that
prevents the release of TGF- and amphiregulin
reverted the malignant phenotype of a breast
cancer cell line in a recent study,43 providing further
proof that inhibition of release of soluble EGFR
ligands can prevent tumor-cell proliferation.
TACE also cleaves heregulin, the ligand for
the HER3 receptor.44 Soluble heregulin binds to
an EGFRHER3 or HER2HER3 receptor dimer
and activates a cell-proliferation pathway.45
A dual inhibitor of TACE and a disintegrin and
metalloproteinase 10 (ADAM10), INCB3619,
has been shown to act synergistically with the
chemotherapeutic agent paclitaxel to reduce tumor
volume in a mouse model of non-small-cell lung
cancer.45 TACE-selective inhibitors have not been
tested in cancer models, even though they might
be less toxic than dual TACEADAM inhibitors.
Shedding of other ErbB receptors might also be
mediated by TACE, and this shedding could result
in constitutively active ligand-independent cell
signaling, as occurs during ADAM processing
of HER2.46
Transactivation of EGFR by G-protein-coupled
receptor (GPCR) agonists is mediated through
ADAM-family members.47 TACE prevents
angiotensin-II-stimulated cleavage of proheparin-binding EGF-like growth factor, EGFR
activation, and cell proliferation in ACHN tumor cells.
Further understanding of how ADAM-family members
contribute to GPCR-mediated transactivation of
EGFRs, and of their role in disease development and
progression, will provide opportunities to develop
novel treatments for cancer.48

cancer than for RA because of possible adverse

effectssince its discovery, TACE has been
reported as a processing enzyme or sheddase for
more than 30 type I and II membrane-spanning
proteins (Table 1).
302 nature clinical practice RHEUMATOLOGY

Preclinical trials with TACE inhibitors

Early preclinical studies indicated that inhib

ition of TACE is beneficial for patients with
arthritis, even though blocking TACE activity
does not neutralize the effects of membranebound precursor TNF. Two dual MMPTACE
inhibitors, GW3333 (compound 1 in Table 2,
Figure 2) from GlaxoSmithKline (GSK)17 and
TMI-1 (compound 2 in Table 2, Figure 2) from
Wyeth,18 proved to be efficacious in various
animal models ranging from arthritis induced
by collagen (collagen-induced arthritis [CIA])
and peptidoglycanpolysaccharide polymer to
the more severe adjuvant-induced arthritis.
More-selective inhibitors by Bristol-Myers
Squibb (BMS, previously Dupont-Merck;
BMS561392; compound 3 in Table 2, Figure 2)19
and Wyeth (TMI-2; compound 4 in Table 2,
Figure 2)20 were also effective in the mouse
CIA model, providing preclinical validation
of TACE as a target for RA therapies. In the
CIA model, paw swelling and erythema are
measured on a scale of 04. In the BMS study,
mice with CIA were given four monoclonal
antibodies against chicken typeII collagen on
day1 followed by lipopolysaccharide (LPS)
on day2. A dose of 10.5mg/kg BMS-561392
twice daily worked as well as etanercept,
reducing the clinical score per paw after 12days
from 1.5 to 0.4. BMS561392 at 2.8mg/kg was
also more effective than infliximab, supporting
the hypothesis that TACE inhibition would
be beneficial for patients with RA. In a study
of the efficacy of TMI-2 in the CIA model,
type II collagen in incomplete Freunds adjuvant was administered on days 0 and 21, and
compound was given twice daily at 100mg/kg
when 10% of the mice developed signs of
arthritis. Paw swelling was reduced from
1.28 to 0.5.
Clinical trials with TACE inhibitors

Recent clinical studies, however, have failed to

show that TACE inhibition is an effective way
of treating RA. For example, in the first phaseII
study from BMS, there were indications that
TACE inhibition induced mechanism-based
toxic effects in the liver.21 The rationale for
designating this toxicity as mechanism-based
stems from the hypothesis that TACE acts
not only on precursor TNF, but also on other
membrane-bound proteins, such as TNF
receptor I (TNFRI) and TNFRII (Figure3).16
A consequent build-up on the cell surface of
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Table 1 Summary of substrates processed by TACE.

Target protein

Function of protein

Indication for TACE inhibitor

Reference

TNF

Mediation of inflammation

Arthritis, Crohns disease, IBD,

diabetes, cardiovascular disease

14, 15

EGF receptor ligands: TGF-, amphiregulin,

epicellulin, epigen

Cell growth and proliferation

Cancer, diabetes, cardiovascular

disease

16, 3941,
49, 50

L-selectin

Leukocyte rolling

Inflammation (prevents cell adhesion)

16, 50

TNFRI and TNFRII

TNF signaling

Hepatotoxicity

16, 50

Collagen XVII ectodomain

Cell adhesion

Cancer (prevents cell spreading)

51

LAG-3

T-cell proliferation

Inflammation

52

Heregulin

Cell growth and proliferation

Cancer

45, 53

IL-1Ra, IL-15Ra

Mediation of inflammation

Rheumatoid arthritis

16, 50

IL-6R

JAKSTAT signaling

Cancer

16

CD40

Immune modulation

Graft rejection

54

NgR, p75NTR

Neurite outgrowth

CNS diseases

50, 55

Neuregulin isoforms

Tumor-cell proliferation

Cancer

53, 56

GPI, (GP)VI and GPIb-IX-V, platelet glycoprotein V

Platelet aggregation and activation

Ischemia, thrombosis

5759

Semaphorin 4D

Regulation of angiogenesis

Cancer

60

SorLA, Vps10-domain receptor family members

Regulation of neurochemistry

Alzheimers disease

61, 62

MUC5AC mucin, MUC1 mucin

Mucus production

Lung diseases

63, 64

APP

Regulation of neurochemistry

Alzheimers disease

65

Nectin-4A

Breast cancer marker

Unknown

66

Hypoxia-induced carbonic anhydrase IX

pH control and cell adhesion

Unknown

67

CX3CL1

Chemotaxis

Autoimmune diseases

68

Endothelial protein C receptor

Anticoagulation

Thrombosis

69

VCAM, ICAM-1

Cell adhesion

Inflammation

70, 71

PAR1 N-terminal exodomain

GPCR for thrombin

Unknown

72

Pref-1

Inhibitor of adipocyte differentiation

Unknown

73

Abbreviations: APP, amyloid precursor protein; CNS, central nervous system; CX3CL1, CX3C-chemokine ligand 1; EGF, epidermal growth factor; GPCR,
Gprotein-coupled receptor; GPI, glycoprotein I; GPIb-IX-V, glycoprotein Ib-IX-V; (GP)VI, platelet collagen receptor; IBD, inflammatory bowel disease; ICAM1,
intercellular adhesion molecule 1; IL-1Ra, interleukin 1 receptor antagonist; IL-15Ra, interleukin 15 receptor antagonist; IL-6R, interleukin 6 receptor; JAK,
Janus kinase; LAG3, lymphocyte-activated gene 3; NgR, Nogo receptor; p75NTR, p75 neurotrophin receptor; PAR1, proteinase-activated receptor 1; Pref-1,
preadipocyte factor1; SorLA, neuronal sorting protein-related receptor; STAT, signal transducer and activator of transcription; TACE, TNF-converting enzyme;
TGF-, transforming growth factor ; TNF, tumor necrosis factor; TNFR, TNF receptor; VCAM, vascular cell adhesion molecule 1.

precursor TNF and of TNFRI and TNFRII

would make cells supersensitive to the effects
of TNF. In a proof-of-concept experiment,
rats were treated with BMS-561392 (a partially
selective inhibitor)19,21 or BMS-566394 (a selective TACE inhibitor; compound5 in Table2,
Figure 2),21 both of which demonstrated
hepatotoxicity. Livers from rats treated with
BMS561392 showed a 10-fold greater accumulation of precursor TNF than those of controls
and a 3-fold greater increase in TNFRII. No data
were presented on the effects of the selective
TACE inhibitor BMS-566394.
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Arguments against mechanism-based toxicity

of TACE inhibitors arise from the fact that,
although TACE is an important physiological
metalloproteinase for processing precursor
TNF, other members of the ADAM family have
been implicated in the processing of TNF receptors.22,23 In one phase I study by GSK, the levels
of soluble TNF, TNFRI and TNFRII in response
to LPS administration were measured before
and after treatment with the metalloproteinase
inhibitor GI5402.24 GI5402 did not affect the
increase in monocyte expression of precursor
TNF or the decrease in granulocyte-membrane
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Table 2 Preclinical and clinical lead compounds for TACE inhibition.

Name (former name)

Originator company
(licensee company)

Mechanism of action

Highest
development phase

Reference

1) GW3333

GSK

TACE and MMP inhibition

Preclinical

17

2) TMI-1

Amgen (Wyeth)

TACE and MMP inhibition

Preclinical

18

3) BMS-561392 (DPC-333)

BMS

TACE inhibition

Phase II

19

4) TMI-2

Wyeth

TACE inhibition

Preclinical

20

5) BMS-566394

BMS

TACE inhibition

Preclinical

21

6) TMI-005 (apratastat)

Wyeth

TACE and MMP inhibition

Phase II

26

7) GW4459

GSK

TACE inhibition

Preclinical

30

8) Compound #51 in Duan et al. (2007)

BMS

TACE inhibition

Preclinical

34

9) W-3646

Wakanuga
Pharmaceutical Co.

TACE inhibition

Preclinical

37

10) Compound #8b in Bandarage et al. (2008)

Vertex

TACE inhibition

Preclinical

38

11) IK682

BMS

TACE inhibition

Preclinical

31

12) GI5402 (GI-245402, BB-2983)

GSK

Nonspecific
metalloproteinase
inhibition

Phase I

24

13) DPC-A38088

BMS

TACE inhibition

Preclinical

32

14) DPH-067517

BMS

TACE inhibition

Preclinical

33

15) R-618

Hoffmann-La Roche

TACE inhibition

Phase I

74

16) CH-138

UCB

TACE, protease, and

MMP inhibition

Preclinical

Unpublished

Abbreviations: BMS, Bristol-Myers Squibb; GSK, GlaxoSmithKline; MMP, matrix metalloproteinase; TACE, TNF-converting enzyme; TNF, tumor necrosis factor.

expression of TNFRI and TNFRII; however, it

did decrease the plasma levels of soluble TNF,
TNFRI and TNFRII. Dupont-Merck carried
out a similar study using BMS-561392 with LPS
in humans and found that precursor TNF and
TNFRI and TNFRII transiently accumulated
on the cell surface of monocytes and T lymphocytes.22 Most of the unprocessed precursor TNF
was degraded after internalization. These two
studies raise some doubt as to whether TACE
inhibition will always lead to toxic effects in
the liver.
The results of the GSK and Dupont-Merck
studies are, however, challenged by evidence that
TACE is also the principal sheddase for TNFRII
as well as for TNF.16 In TACE knockout mice, the
level of circulating TNFRII in the serum is over
90% lower than that in wild-type mice, whereas
TNFRI levels are approximately 50% lower.25
For many shedding processes, the ADAM-family
members that seem to be active during constitutive release of membrane proteins differ from
those that are active during induced release. In
addition, the use of particular family members
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might depend on the cell type. The release of

membrane proteins by ADAM proteins can,
therefore, be quite complicated, and often
multiple enzymes are involved.
In a phase II study of the dual MMPTACE
inhibitor TMI-005 (compound 6 in Table 2,
Figure 2), also known as apratastat, no hepatotoxicity was found, but the efficacy results were
discouraging.26 This was a 12-week, randomized
placebo-controlled, phase II study, in which 390
patients with RA were treated with both methotrexate and TMI-005 (given orally three times
daily at 50, 100 or 150mg). There were seven
adverse events in the treated group compared
with none in the placebo group; however, none
of the participants developed an increase in the
levels of hepatic aminotransferases, ruling out
hepatotoxicity. In addition, the treated patients
showed no improvement in symptoms relative to patients in the placebo group. The lack
of efficacy of TMI-005 might partly result from
basal signaling via TNF receptors by membranebound precursor TNF on immunological cells.
Dosing was probably adequate, as this trial
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1) GW3333

3) BMS-561392 (DPC-333)

2) TMI-1
O

OH
N

H
N

HO
N
H

HO

H
N

O
OH

CF3
N

HO

H
N

N
O

O
N
H

NH
O

NH
HN

N
H

O
N+

O
HN

10) Compound #8b in Bandarage et al. (2008)38

9) W-3646

O
N

S
O
N

O
HO

N O

S
O

N
H
N

NH
O

11) IK682

O
O S

SH

N
H

OH

O
OO S
N
S

8) Compound #51 in Duan et al. (2007)34

OH
H

6) TMI-005 (apratastat)

7) GW4459

HN
HO

5) BMS-566394
O
H
N
HO
O HN

N
H

O NH2

4) TMI-2
O

N
H

O O S
N

HN
HO

N
O

Figure 2 Structural representation of preclinical and clinical lead compounds for TACE inhibition. The available structures for
compounds detailed in Table 2 are outlined. The structures for compounds 1216 in Table 2 are unavailable. Abbreviation: TACE,
TNFconverting enzyme.

followed protocols established in a phase I study

that used LPS in human individuals to determine the levels of TMI-005 that were needed in
the blood to inhibit TNF release from immunecompetent cells. On the basis of the phase II
results, the development of TMI-005 by Wyeth
was terminated. Although this study showed
that dual inhibition of TACE and MMPs was not
beneficial for the treatment of RA, it did provide
impetus for the use of TACE inhibitors for other
indications. The development of TMI005 for
other indications is unlikely, however, as cases
of tendonitis were reported. This condition
is reminiscent of that occurring in cancer

patients treated with MMP inhibitors such

as marimastat.27 This adverse effect probably
occurs because TMI-005 is a broad-spectrum
MMP inhibitor.
CHEMISTRY OF TACE INHIBITION

TACE inhibitors were initially nonspecific

and also targeted MMPs. For example, GSKs
GW3333 (compound 1 in Table 2, Figure 2)
inhibits TACE, MMP1, MMP2, MMP3, MMP8,
MMP9 and MMP13,17,28 and was undergoing
preclinical studies as an orally active therapy
for RA. GSK stated that GW3333 was the first
inhibitor with sufficient duration of action to

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Cell membrane

ADAM TNFRII

TNFRI

Endogenous
neutralizing
receptors
TACE
inhibitor

sTNFRII

sTNFRI
sTNF

TACE

proTNF

Figure 3 Processing of TNFRI and TNFRII by TACE and other ADAM-family

members. TACE can process TNFRI and TNFRII to generate the soluble
receptors sTNFRI and sTNFRIIthese soluble forms help to neutralize the
effect of TNF. TACE seems to be the major convertase for precursor TNF and
for TNFRII, whereas unidentified ADAMs also process TNFRI. When TACE is
inhibited, membrane-bound forms of TNF, TNFRI and TNFRII can potentially
build up on the cell surface, leading to sensitization of the cells to precursor
TNF and the potential for liver toxicity. Abbreviations: ADAM, a disintegrin
and metalloproteinase; proTNF, precursor TNF; sTNF, soluble TNF; sTNFRI,
soluble TNF receptor I; sTNFRII, soluble TNF receptorII; TACE, TNF-converting
enzyme; TNF, tumor necrosis factor; TNFRI, TNF receptor I; TNFRI, TNF
receptor II.

chronically inhibit TACE and MMPs in the rat.

The compound also has the potential to cause
tendonitic adverse effects, however, as it is not
selective for TACE over other MMPs, and also has
low solubility in gastric fluid. The development of
GW3333 and more recent orally available TACEselective inhibitors29 has been discontinued. The
terminated studies include GSKs program for
optimization of GW3333, in which GW4459
(compound 7 in Table 2, Figure2) was identified
as a potent (IC50=4.3nM) TACE inhibitor with
selectivity over MMP1 and MMP3 and high solubility in gastric fluid,30 and a study of another
potent and selective orally available TACE
inhibitor, which has 5-methyl-thienylalanine
and threonine side chains in the reverse hydro
xamate series.29 Wyeth also was developing
orally active, small-molecule inhibitors of TACE
for the treatment of RA. TMI-1 (compound 2
in Table 2, Figure 2) is one orally available,

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small-molecule dual inhibitor of TACE and

MMPs that was developed.18
BMS-561392 (compound 3 in Table 2,
Figure2) is an orally active, partially selective
inhibitor of TACE.19 It also targets MMP3 and
MMP12 as well as ADAMTS4 (ADAM with
thrombospondin motifs 4).21 BMS-561392 is a
gamma-lactam analog of the nonpeptide, smallmolecule selective TACE inhibitor IK682.31 In
animal models, it functions as a DMARD. BMS561392 originated at Dupont-Merck and was
being developed by BMS. It was the first partially
selective TACE inhibitor to reach phaseII
clinical trials for the treatment of RA and was
tested in the preclinical setting for inflammatory
bowel disease.
BMS has synthesized a series of structurally
diverse TACE inhibitors as potential backup
compounds to BMS-561392. At the 228th
National Meeting of the American Chemical
Society in 2004, BMS researchers announced
the development of potent and selective
TACE inhibitors from a series of -benzamido
hydroxamic acids.32 The lead compound,
DPCA38088, demonstrated potent binding and
a good pharmacokinetic profile in rats and dogs.
Another TACE inhibitor, DPH-067517, was
under development by BMS for the treatment of
cerebral ischemia.33 Duan et al. discovered a new
series of TACE inhibitors by using a pyrimidine2,4,6-trione as a hydroxamate replacement.34
Even though pyrimidine-2,4,6-trione is a
markedly weaker ligand for the zinc ion than is
hydroxamic acid, highly potent TACE inhibitors
have been identified through optimization of the
rest of the molecule. The most potent compound
reported (compound 8 in Table 2, Figure 2)
had an IC50 of 2nM. Despite the success of
BMS in producing selective TACE inhibitors
with drug-like properties, their program,
including the development of BMS-561392,
has been discontinued because of concerns over
mechanism-based liver toxicity.
Several elegant structure-based methods and
structureactivity relationship optimization
programs have generated new potent, selective and orally bioavailable TACE inhibitors.
These agents include piperidine -sulfone
hydroxamates (Wyeth)35 and -benzamido
hydroxamic acids (BMS).36 These compounds
are at very early stages of preclinical studies.
The most recent partially selective TACE
inhibitor to advance into the clinic was
TMI005 (detailed in text above);20 however, its
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development has been discontinued, in part

owing to lack of efficacy. Other companies
have produced TACE inhibitors that have
subsequently been discontinued; for example,
Hoffmann-La Roche (R-618), UCB (CH-138),
and Wakanuga Pharmaceutical Co.37 (W-3646;
compound 9 in Table 2, Figure 2). Some companies, however, are running programs that are still
considered to include active TACE inhibitors,
such as those operated by Vertex38 (thiol-based
TACE inhibitors [e.g. compound 10 in Table 2,
Figure 2]) and Wyeth. Bayer Schering Pharma
has filed several patent applications with very
broad claims that indicate their activity in
this field (WO2005/121130, US2006/0178366,
US2006/0252778, US2007/0167426).
One of the main hurdles to overcome in
chemistry programs is the issue of why low
nanomolar inhibitors of TACE dont necessarily translate to inhibitors with good activity in
cells and human whole blood. This discrepancy
is thought to arise because inhibitors need to
penetrate through or into the cell membrane
to inhibit TACE. In complex systems, such as
cell-based assays, competition for the inhibitor
might occur following protein binding.
CONCLUSIONS

Since the validation of anti-TNF therapy for

the treatment of RA, much effort has gone into
making small-molecule inhibitors that lack the
cost and adverse effects associated with current
large biomolecules. Researchers have actively
sought out pharmacological targets that are
amenable to the production of orally available drugs. One such target, TACE, was chosen
because it processes membrane-bound precursor
TNF to generate a soluble form of the cytokine
that can act both in an autocrine manner and
distally from the producing cells. The discovery
of TACE permitted pharmaceutical companies to convert nonselective metalloproteinase
inhibitors into selective compounds with druglike properties. In spite of the many failures,
two TACE inhibitors progressed into the clinic
for treatment of RA. Unfortunately, the clinical
trials were terminated in phase II because of
mechanism-based hepatotoxicity and/or lack
of efficacy.
Much research on the biology of TACE has
been carried out since its discovery. Thought
of initially as a selective enzyme that processes
only precursor TNF, TACE is in fact quite
promiscuous and can cleave approximately 30
june 2008 vol 4 no 6 MOSS ET AL. 

membrane-spanning proteins. Clearly, inhib

ition of TACE might be more suitable for
diseases such as cancer, in which potential drugs
often have a toxicity profile that is less than ideal
(Box 1). In the next 10years researchers will
probably determine whether selective TACE
inhibitors can stand alone as therapy for RA
or other diseases such as cancer, diabetes, and
cardiovascular diseases.
KEY POINTS

Biologic anti-tumor necrosis factor (TNF)

agents, including etanercept, infliximab and
adalimumab, reduce the severity of symptoms
for individuals with rheumatoid arthritis (RA)

There is still an unmet medical need for orally

available, small-molecule inhibitors of TNF

TNF-converting enzyme (TACE) has been

validated in preclinical models for the treatment
of RA

Clinical trials have not determined whether

TACE inhibitors have a suitable efficacy or
toxicity profile for use in patients with RA

TACE-selective inhibitors have been made, and

could be used in the future as therapeutics

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Acknowledgments
We thank R Black for
comments and suggestions
on the manuscript.

Competing interests
The authors declared no
competing interests.

nature clinical practice RHEUMATOLOGY 309