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Available online at www.sciencedirect.com

The therapeutic potential of phosphatase inhibitorsViktor V Vintonyak1, Andrey P Antonchick1, Daniel Rauh3 and HerbertWaldmann1,2

Protein phosphatases (PPs) constitute a large family of

enzymes, which are crucial modulators of cellular

phosphorylation events. Malfunction in PP activity has been

associated with human diseases, including diabetes, obesity,

cancer, and neurodegenerative and autoimmune disorders,

and makes this class of enzymes attractive targets for chemical

biology and medicinal chemistry research. A number of

strategies are currently explored for the identification and

development of various classes of PP modulators and have

resulted in a plethora of chemically distinct inhibitors. Limited

selectivity and adverse pharmacological properties of PP

inhibitors are still major bottlenecks for further clinical

development and resulted in only a few molecular entitiescurrently in clinical trials.

Addresses1 Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11,

D-44227 Dortmund, Germany2 Technical University Dortmund, Otto-Hahn-Strasse 6, D-44221Dortmund, Germany3 Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany

Corresponding author: Rauh, Daniel ([email protected]) and

Waldmann, Herbert ([email protected])

Current Opinion in Chemical Biology 2009, 13:272283

This review comes from a themed issue on

Next-generation therapeutics

Edited by Karl-Heinz Altmann and Dario Neri

Available online 4th May 2009

1367-5931/$ see front matter# 2009 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.cbpa.2009.03.021

IntroductionPhosphorylation and dephosphorylation are among the

most important modifications by which nature modulatesprotein function in nearly all biological systems to trans-

duce information between distinct cellular sites. The

specific transfer of theg-phosphate from ATP to substrate

proteins is catalyzed by protein kinases (PKs) and can

lead to conformational changes, promote proteinprotein

interactions, or turn on/off enzymatic activity to allow

cells to translate a wide variety of environmental signals

into functional changes. Protein phosphatases (PPs) are

defined by their ability to catalyze the hydrolysis of

phosphates to restore the protein substrate to its depho-sphorylated state and can be considered as physiological

counterparts of PKs. The balanced and highly dynamic

interplay between these two enzyme classes is crucial for

the control of cell signaling cascades. To achieve the

essential temporal and spatial specificity in modulating

enzyme activity in signaling events, nature often uses the

compartmentalization of PK and PP activities. In con-

sequence, aberrantly regulated PKs and PPs play causa-

tive roles in diseases such as cancer, diabetes, and

neurological and autoimmune disorders, making these

enzymes an important set of therapeutic targets across

almost all disease areas [1,24,5,6]. PPs are classified

by their substrate specificities into serine/threonine-phos-

phatase (STP), protein histidine-phosphatase (PHP),protein tyrosine-phosphatase (PTP) and dual-specific

phosphatases (DSPs) which catalyze the dephosphoryla-

tion of both serine/threonine or tyrosine residues. The

detailed understanding of the different catalytic mech-

anisms, substrate specificities, and associated confor-

mational changes in phosphatase structure has provento be crucial for the design and development of potent

and selective inhibitors. STPs have metal ions in their

catalytic center (zinc, manganese, or magnesium) which

are coordinated by side chains of His and Asp amino acids.

A highly polarized water molecule bridges the two metal

centers and can act as a nucleophile attacking the phos-

phate group to initiate its hydrolysis. PTPs follow adifferent mechanism and do not require metal ions. A

structural characteristic crucial for the design of most PTP

inhibitors is a deep pocket to accommodate the pTyr of

the substrate. A WPD-loop (Trp-Pro-Asp) closes on this

site, regulates catalysis by its Asp residue, and allows

proper substrate recognition. In the closed substrate

bound state, the Asp forms a hydrogen bond to the

phenolic oxygen of the pTyr and polarizes this site for

the nucleophilic attack of the adjacent catalytic cysteine.

This Cys is positioned at the N-terminus of a long helix in

the middle of the catalytic domain. The helix induces adipole and thereby alters the properties of the Cys thio-

late side chain. The phosphate gets transferred onto the

Cys to form a thiophosphate, which is subsequentlyhydrolyzed by a water molecule. DSPs follow the same

mechanism but possess a shallower substrate pocket to

accommodate pThr and pSer.

The human genome encodes for a total of 518 kinases,

including 90 tyrosine kinases. Similarly, more than 130

PPs are encoded in the human genome, including 107

tyrosine phosphatases [7]. This represents a fairly

balanced complement of PTKs and PTPs and suggests

an equal partnership of these enzymes in regulating

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protein function through tyrosine phosphorylation. Themajority of protein phosphorylation, however, occurs on

serines and threonines and is catalyzed by the remaining

428 protein serine/threonine kinases. The fewer protein

STPsimply thatthese enzymes mustdisplaymuch broader

substrate specificities than the complementary kinases.The catalytic domains of PPs are highly conserved and

differences in substrate specificity are largely determined

by regulatory domains or subunits. Somecatalytic domains,

in particular those of the protein STPs, can interact with a

large variety of regulatory subunits and are controlled by

post-translational modifications, proteinprotein inter-

actions, or heteromeric compositions. The incorporation

of catalytic subunits in multidomain complexes explains

why eukaryotes contain fewer genes that encode for PPs

than genes that encodefor PKs. When theholoenzymesare

considered, the numbers of PKs and PPs are more or less

balanced [3,810]. PPs are often kinase substrates them-

selves, underlining their essential regulatory role in sig-

naling cascades. As a consequence, many diseases have

beenshown to be associated withregulatory malfunction of

PPs and the acceptance of PPs as equal in importance to

PKs as potential drug targets has been supposed over the

last decade. In this review we will focus on recent progress

in the development of inhibitors directed against clinically

relevant PPs (Table 1).

Clinically relevant phosphatasesPTP1B

Acquired Type 2 diabetes and obesity often can be

considered as lifestyle-related diseases of civilization

and are linked to insulin resistance and loss of proper

glucose homeostasis. Type 2 diabetes and obesity areoften coupled in human and can lead to the metabolic

syndrome, which dramatically increases the risk of cardi-

ovascular incidences and decreases lifespan. Some pre-

dictions for the year 2015 estimate 70% of the population

of the western hemisphere to be overweight and 40% of

these to be obese. The social impact and costs associated

with this health risk will be substantial and drugs regulat-ing metabolic disorders are in high demand.

The discovery of the receptor tyrosine phosphatasePTP1B as a negative regulator of the insulin and leptin

receptor pathways [11,12,13] and animal studies demon-

strating that PTP1B-deficient mice show an enhanced

insulin sensitivity, improved glycemic control, and resist-

ance to high fat diet induced obesity [14

,15] made thisenzyme an attractive drug target. Although the molecular

causality of insulin resistance and obesity is not fully

understood, the hormone insulin induces autophosphor-

ylation of its receptor and thereby triggers a kinase

cascade that finally induces synthesis of the short-term

energy storage glycogen and synthesis of fatty acids and

proteins. Dephosphorylation of the receptor by PTP1B

leads to its inactivation and shut-down additional down-

stream processes. The pharmacological blockage of

PTP1B should therefore counteract insulin resistance.

At the latest when Abbott demonstrated that antisense

oligonucleotides (ASOs) designed to downregulate

expression of PTP1B normalized blood glucose and

improved insulin sensitivity without changing the regular

diet of mice [16], nearly every major pharmaceutical

company launched a program for the identification of

potent PTP1B inhibitors. Besides its central role in the

insulin cascade PTP1B is also involved in a variety of

clinically relevant pathways [17,18] and is overexpressed

or upregulated in human breast, colon, and ovarian can-

cers [1921]. However, the discovery of clinically useful

PTP1B inhibitors has proven to be very difficult because

of limited inhibitor selectivity and low bioavailability

[4,5,22].

Structure-based design and active-site inhibitors

Structure-based design is widely applied to phosphataseinhibitor research and best exemplified by more than 80

complex crystal structures of PTP1B deposited in the

Protein Data Base (PDB) (Figure 1a). One of the first

crystal structures of PTP1B (pdb code: 1pty) featured an

enzymatically dead mutant variant (catalytic Cys mutated

to Ser) in complex with phosphotyrosine. The substrate is

coordinated in the active site of the phosphatase by anetwork of hydrogen bonds. Interestingly, a second pTyr

Therapeutic potential of phosphatase inhibitors Vintonyak et al. 273

Table 1

Selected phosphatases as target proteins

Family Phosphatases Disease, therapeutic approachSerine/t hre onine phospha tases PP1, PP2A Tumor suppression, malignancy

PP2B, PP2C Cystic fibrosis, immune suppression, asthma, cardiovascular

Tyrosine phosphatases PTP1B Diabetes, obesity

MptpA/B Tuberculosis

CD45 Alzheimers disease, autoimmune disease, inflammation,

organ transplantationSHP-1/2 Neuron protection, obesity, Noonan syndrome, leukemia,

regulation of RAS/MAP-kinases

Dual-specific phosphatases VHR Regulation of MAP-kinases

Cdc25 Cell cycle progression, tumor therapy (various human cancers)

PRL-1/2/3 Promoting tumor cells, leukemia, Hodgkins disease, prostate cancer

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molecule was identified in an adjacent, noncatalytic site

and stimulated ideas to fuse the two moieties by a suitable

linker which resulted in bidentate inhibitors with

dramatically increased affinities (Figure 1b). This second

site has since then been highly important in lead structureoptimization for PTP1B. Fragment-based approaches

both by protein X-ray crystallography and NMR tech-

niques were employed to identify, for example, small

organic acids as binders to this second site and resulted in

an impressive array of potent nM inhibitors when fused to

phosphomimics (Figure 2).

Most active-site-directed PTP inhibitors reported to date

are nonhydrolyzable pTyr mimics that take advantage of

the positively charged active site. However, this con-

served mode of action reduces selectivity and often

results in the potent inhibition of multiple phosphatases.

Most pTyr mimics possess a high charge density, which in

turn is often detrimental to cell penetration. The most

useful and potent pTyr surrogate devised for PTP1B thus

far contains the nonhydrolyzable difluorophosphono-

methylphenylalanine (F2Pmp) group [23]. The fluorine

atoms have been proposed to interact via hydrogen bonds

with NH-groups of the PTP and to increase the binding

affinity by several orders of magnitude. Compound 1a

identified from a combinatorial chemistry approach dis-

plays a Ki value of 2.4 nM for PTP1B and exhibits notableselectivity in favor of PTP1B against a panel of PTPs

including Cdc25A, SHP-2, and VHR [24]. Because of its

high polarity compound 1a is not cell permeable and

shows no cellular activity. To enhance penetration across

membranes, derivatives of 1a were prepared either by

coupling to a cell permeable (D)-Arg8-peptide tag (1b)[25] or to a highly lipophilic fatty acid (1c) [26]. Com-

pound 1b showed a significant improvement in leptin-

dependent suppression of food intake in leptin-resistant

rats [27]. Furthermore, the concept of a prodrug was

utilized in 2 [28].

Several strategies have been applied to identify pTyr

mimics with more favorable pharmacological properties.

One such approach, referred to Breakaway Tethering,

introduces a Cys residue on the surface of the enzyme,

which acts as a tethering point. The modified enzyme is

274 Next-generation therapeutics

Figure 1

Inhibitors in complex with the catalytic domain of PTP1B. (a) 88 PTP1B-inhibitor complexes found in the PDB and aligned to the first reportedPTP1B crystal structure (PDB code: 1pty). Most inhibitors target the phosphate binding sites and mimic substrate binding. (b) Close-up

view of the active site shows binding of the pTyr of the substrate peptide (gray sticks) to the N-terminal end of the central helix (blue) to

position the phosphate in close proximity to the catalytic Cys215 (ball and sticks). The WPD-loop (yellow) controls access to the active

site. Binding of a second pTyr molecule (blue ball and sticks) adjacent to the active site stimulated the design of molecules that bind toboth pTyr sites and resulted in the development of the potent bidentate inhibitor 8 (green) (PDB code: 2qbp). (c) In inactive PTP1B

conformations the C-terminal helix (orange) adopts an extended orientation and exposes a new cavity (green). Allosteric modulators

such as 3 inhibit PTP1B activity by binding to this allosteric site and preventing the WPD-loop from adopting a catalytically competent

conformation. The inhibitors bind around the side chain of Phe280 and form favorable pp interactions. Figures were prepared with PyMol(http://www.pymol.org).

http://www.pymol.org/http://www.pymol.org/

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Figure 2

Structures of selected PTP1B and Cdc25 inhibitors, IC50 or Ki values are given.


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incubated with a library of disulfide-containing small-molecule fragments under reducing conditions, which

promote thiol exchange and formation of an SS bond

between the ligand and the surface Cys residue [ 29].

This tethering approach in combination with mass spec-

trometry allows for capturing compounds that displayeven weak affinity for the target protein. Using this

approach Erlanson et al. identified a novel PTP1B inhibi-

tor with enhanced bioavailability.

In a more recent analysis 1,2,5-thiadiazolidin-3-one-1,1-

dioxide was identified as a novel phosphomimic and the

isothiazolidinone group was utilized in the synthesis of the

peptide-based inhibitor 4, which shows an IC50 of 40 nM[30]. In addition, using the samemimic, nonpeptide-based

compound 5 was identified, which displays high potency in

biochemical assays (IC50 of 35 nM). The same compound

also shows cellular activity and increases the level of

phosphorylation on the insulin receptor (2.8-fold) at

80 mM [31]. More recently, Zhang et al. identified aryl

diketoacids 6 as novel pTyr surrogates and showed that

neutral amide-linked aryl diketoacid dimers 7 also exhibitPTP inhibitory activity. Detailed studies by enzyme

kinetics and protein X-ray crystallography revealed that

these derivatives stabilize PTP1B in its inactive, WPD-

loop open conformation and act as noncompetitive inhibi-

tors [32]. Using a high-throughput screening approach a

series of monocyclic thiophenes were identified as PTP1B

inhibitors [33]. Further optimization resulted in the de-

velopment of the potent inhibitor 8. Introduction of a

tetrazole ring or 1,2,5-thiadiazolidine-3-one-1,1-dioxide

as a carboxylate mimic led to the discovery of two unique

starting points that improved cell permeability andincreased potency up to 300 nM [34]. Additional examples

for active-site-directed PTP1B inhibitors include arylben-

zonaphthothiophenes and arylbenzonaphthofurans. Both

scaffolds were shown to improve insulin sensitivity in

rodents. One compound from these efforts, ertiprotafib

(9), progressed to clinical trials for the treatment of Type 2

diabetes. Development was discontinued in phase IIbecause of insufficient efficacy and strong unwanted side

effects [35]. Although great progress has been made to

increase potency of PTP1B inhibitors, initial successes

were compromised by unwanted cross reactivity with T-

cell protein tyrosine phosphatase (TCPTP) (77%

sequence identity with PTP1B) and the discovery thatTCPTP knockout mice are born healthy but die after

about four weeks. Even more disturbing was the finding

that parallel knockoutof TCPTP andPTP1B turnedout to

be lethal. The design and synthesis of selective PTP1B

inhibitors that are less potent against TCPTP can be

considered a particular challenge in current PTP1B med-

icinal chemistry research.

Allosteric inhibitors

An alternative approach to overcome the current limita-tions in selectivity and bioavailability of active-site-

directed phosphatase inhibitors was presented in 2004when researchers at Sunesis reported an allosteric site

located at the back of the phosphatase about 20 A distant

to the catalytic site. The crystal structure of PTP1B in

complex with the allosteric inhibitor 3 (pdb code: 1t4j)

proved that the ligand stabilizes the inactive phosphataseconformation by preventing the WPD-loop from adopting

a catalytically competent conformation [36] and

revealed a novel but general mechanism to inhibit tyro-

sine phosphatases (Figure 1c). In the allosteric site, the

inhibitor binds close to a central Phe residue and forms

favorable pp interactions. Interestingly, the structural

homolog TCPTP holds a Cys residue at this position and

3 binds only with reduced affinity. Future work will show

if the selectivity problem can be tackled adequately by

this new mode of action. Another allosteric inhibitor of

PTP1B, trodusquemine (MSI-1436) (10), is being devel-

oped by Genaera Corp. for the potential treatment of

Type 2 diabetes and obesity and proceeded to phase Ib

[37]. Two previous phase I studies showed that single

doses of10 administered to more than 60 subjects were

well-tolerated with an acceptable adverse event profile,

produced dose-dependent weight loss and improved

insulin sensitivity. Genaera Corp. expects to verify the

clinical potential and positive efficacy results of this drug

in ongoing clinical trials [38].

Meanwhile a new clinical focus is on ASOs which are

directed against PTP1B. The main advantage of oligo-

nucleotides compared to small-molecular-weight inhibi-

tors is their genetic selectivity for PTP1B without perturbing

TCPTP function. Several PTP1B ASOs have been devel-

oped by ISIS Pharmaceuticals Inc. and a second gener-ation ASO ISIS-113715 is currently in phase II clinical

trials for the treatment of Type 2 diabetes.

Cancer-related PTPs

A number of PTPs have been identified as critical onco-

genes in human malignancy and are considered potential

drug targets for the development of novel anticancertherapeutics [5,6,39,40].

Cdc25

Cdc25s belong to the family of DSPs and regulate cyclin-

dependent kinases (Cdks), which are the key participants

in cell division induced in response to extracellular signalsincluding growth factors. Cdc25 phosphatases are also the

key components of the checkpoint pathway and are

inactivated or degraded to induce cell cycle arrest in

response to DNA damage, leading to DNA repair or

apoptosis [41]. Dysregulation of these processes can

contribute to genomic instability and lead to cancer. In

humans, the three isoforms Cdc25A, Cdc25B, and

Cdc25C seem to have overlapping substrate specificities

for the different Cdkcyclin complexes [42]. Cdc25A and

Cdc25B overexpression has been reported in varioushuman cancers, including breast, ovarian, prostate, lung,



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colorectal, pancreatic, gastric, thyroid, hepatocellular, andneuroblastoma and often put in context with more aggres-

sive tumors and poorer clinical outcome [41]. The

inhibition of Cdc25 phosphatases may represent a novel

approach for the development of anticancer therapeutics.

Two recent reviews by Garuti et al. [43] and Contour-Galcera et al. [44] provide a comprehensive overview of

current Cdc25 inhibitor development. The most potent

Cdc25 inhibitor reported to date is the naphthoquinone

NSC95397 (11) with IC50 values of 22, 125, and 56.9 nMfor Cdc25A, Cdc25B, and Cdc25C, respectively [45]. In

addition, it displayed significant inhibition when tested

against human and murine carcinoma cells and blocked

the G2/M phase transition during the cell cycle. Another

potent compound is NSC663284 (12), which inhibits

Cdc25s in vitro in an irreversible, time-dependent manner

with Ki values in the mid nM range for all Cdc25 isoforms.

It arrests cells in the G1 and G2/M phases of the cell cycle

and induces significant growth inhibition of human breast

cancer cell lines [46]. Contour-Galcera et al. recently

reported the identification of a new thiazoloquinone,

BN82685 (13), which inhibits Cdc25 in biochemicalassays (IC50 = 250, 250, and 170 nM for Cdc25A, Cdc25B,

and Cdc25C, respectively) and is active against human

xenografts [47]. In addition, low concentrations of

BN82685 in combination with the mitotic inhibitor pacli-

taxel (Taxol) inhibit the proliferation of colon cancer cells

[48]. Most quinone-based Cdc25 inhibitors reported to

date are irreversible binders and act via arylation of the

nucleophilic catalytic Cys. The redox properties of qui-

nones can also generate reactive oxygen species (ROS),

which may cause toxicity to normal tissues and thus

reduce therapeutic potential. In order to overcome thisproblem, Carr et al. recently synthesized a series of non-

quinone sulfone analogs of vitamin K3, H32 (14) [49].

Such compounds preferentially inhibit Cdc25 by rever-

sibly binding to the catalytic cysteine and lead to G1

phase arrest during the cell cycle in Hep3B cells. An

alternative strategy in the design of Cdc25 inhibitors is

the utilization of phosphate surrogates, which anchor theligand in the active site. Dysidiolide (15a), a sesterterpe-

noid isolated from the Caribbean sponge Dysidea etheria

was the first natural product reported to be active on

Cdc25 (inhibition of Cdc25A with an IC50 of 9.4 mM). The

g-hydroxybutenolide moiety is thought to mimic the

substrate phosphate. Facilitating 15a as a biologicallyvalidated starting point, we used solid-phase synthesis

for the generation of a small collection of dysidiolide

analogs [50,51] and were able to identify the inhibitors

of Cdc25C that are more potent than the parent natural

product 15a. Analogs 15b and 15c displayed IC50 values of

5.1 and 0.8 mM, respectively. Moreover, these analogs

proved considerable biological activity in cytotoxicity

assays employing different cancer cell lines. Using the

structures of dysidiolide and vitamin D3 as starting points

Shimazawa et al. designed several potent Cdc25 inhibi-tors. Compound 16 inhibits Cdc25A and Cdc25B with

IC50 values of 0.44 and 1.9 mM, respectively [52]. Recently2-methoxyestradiol (2-ME) was reported as a potent,

selective, and relatively nontoxic inhibitor of hepatoma

growth both in vitro and in vivo. It was suggested that 2-

ME binds to the catalytic site Cys [53]. Another class of

Cdc25 inhibitors is maleic anhydride derivatives bearing afatty acid chain at the C-4 position [54]. Compound 17

inhibits Cdc25s with IC50 values in the low mM range and

induces G0/G1 phase accumulation with subsequent

inhibition of Cdk2 activity. Moreover, apoptosis was

triggered in the presence of17 within a 48-hour treatment

without oxidative burst. N-Arylmaleimide derivatives are

potent electrophiles and reagents for thiol-selective

modifications and were introduced as a novel class of

Cdc25 inhibitors [55]. PM-20 (18) is selective for Cdc25A

with an IC50 value of 1 mM. Furthermore, PM-20 inhibits

the growth of several human tumor cells, especially

Hep3B cells with an IC50 of 0.7 mM. More recently several

Cdc25 phosphatase inhibitors with micromolar activities

were discovered from structure-based virtual screening

[56]. The most active of them was compound 19, which

inhibits Cdc25A and Cdc25B with IC50 of 0.8 and 2.0 mM,respectively.

SHP-2

SHP-2 is a nonreceptor PTP that mediates cell signaling

by growth factors and cytokines acting via the RAS/MAP-

kinase pathway [40]. Consistent with its overall role in cell

signaling, mutations of the SHP-2 gene (PTPN11) can

cause hyperactivation of its catalytic activity and have

been identified in the Noonan syndrome, a developmen-

tal disorder that is frequently associated with short stature

[57], and in various childhood leukemia [58]. The inci-dence of the Noonan syndrome is relatively frequent and

affects 1 in 1002500 children, while leukemia accounts

for 2% of adult cancers and 1/3 of childhood cancers.

Because mutation associated SHP-2 overactivation seems

to be the cause of a great portion of these incidents,

pharmacological modulation of SHP-2 activity represents

an attractive way to prevent disease development inpatients bearing these mutations. The exploration of

selective SHP-2 inhibitors not only is thought to be of

use for the treatment of cancer but may also become the

basis for future treatments of infectious diseases. The

pentavalent antimony derivative sodium stibogluconate,

a known agent against leishmaniasis, has recently beenfound to inhibit SHP-2 activity [59]. Moreover, sodium

stibogluconate is the first SHP-1/2 inhibitor that reached

the clinic. In September 2006 VioQuest Pharmaceuticals

initiated a phase I/IIa clinical trial for sodium stiboglu-

conate as chemotherapeutic in patients with advanced

malignancies. Although SHP-2 represents an attractive

target for the treatment of cancer, only a few SHP-2

inhibitors are known from the literature. Recently the

design and synthesis of a compound collection containing

SHP-2 inhibitors inspired by furanodictines and the con-cept of biology-oriented synthesis was reported [60].



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Inhibitor 20 (Figure 3) exhibits an IC50 of 2.5 mM against

SHP-2. A screening initiative at the National Cancer

Institute resulted in the identification of NSC-87877

(21) [61] and NSC-117199 (22) [62] which inhibit SHP-

2 with IC50 values of 0.32 and 47 mM, respectively. On the

basis of the oxindole 22 a focused library was designed

and 23 was identified as a selective inhibitor of SHP-2

over SHP-1 and PTP1B with an IC50 value of 0.8 mM for


Figure 3

Structures of selected inhibitors of SHP-2, PRLs, MptpA, MptpB, and CD45. IC50 or Ki values are given.


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SHP-2 [62]. Recently, Birchmeier et al. performed an in

silico screen of low-molecular-weight compounds that

may bind to the catalytic site of SHP-2. This analysis

resulted in the discovery of PHPS1 (24) as a potent and

cell-permeable inhibitor, which is selective for SHP-2

over SHP-1 and PTP1B [63]. PHPS1 efficiently inhibitsthe activation of Erk1/2 by a leukemia-associated mutant

variant of SHP-2 and blocks growth of a variety of human

tumor cell lines. In addition, Geronikaki et al. reported the

synthesis and biological evaluation of thiazolidin-4-one

derivatives as a novel class of SHP-2 inhibitors [64].

Compound 25 exhibited the best inhibitory activity with

a Ki of 11.7 mM.

PRL

Members of the phosphatase of regenerating liver (PRL)

subfamily are DSPs, consisting of PRL-1, PRL-2, and

PRL-3, and represent an intriguing group of potential

target proteinsfor the treatment of various cancers [6,65].

PRL-3overexpression correlates withmetastasis in many

malignancies and several recent reports suggest that

PRLs may play key causal roles in promoting tumor cellmotility and invasion. PRL-3 expression is upregulated

in the tumors of colorectal cancers metastasized to liver

[66], brain, lung, or ovary [67] and is also elevated in

pediatric acute myeloid leukemia, Hodgkins lymphoma

cells, and prostate cancer. In addition, alteration of PRL-

1 expression in a number of cancer cell lines leads to

changes in cell adherence and invasive properties. The

genetic knockdown of PRL-3 with interfering RNA in

cancer cells can abrogate cell motility and the ability to

metastasize in a mouse model [68]. However, the dis-

covery of PRL phosphatase inhibitors has lagged behindthe extensive pharmacological and structural studies on

this target protein and only a few inhibitor classes have

been reported so far. The bis-benzamidine derivative

and antileishmaniasis drug pentamidine (26) were

reported to inhibit all three PRL isoforms in vitro and

induced tumor shrinkage in a melanoma mousexenograft

model [69]. In addition, recent studies by Lee et al.

showed that the combination of pentamidine with the

phenothiazine antipsychotic agent chlorpromazine

exerts synergistic antiproliferative effects. Pentamidine

treatment resulted in chromosomal segregation defects

and delayed progression through mitosis, which is con-

sistent with the inhibition of PRL [70]. Another class ofPRL-3 inhibitors was identified by screening of chemical

libraries by Ahn et al. Benzylidene rhodanine derivatives

showed good inhibitory activity against PRL-3. Com-

pound 27 was the most active with an IC50 of 0.9 mM in

vitro and showed reduced invasion in cell-based assays

[71]. In addition, biflavonoids isolated from young

branches of Taxus cuspidata inhibit PRL-3 with IC50values in the low mM range [72]. More recently Park

et al. identified 12 novel inhibitors of PRL-3 by means of

virtual screening and docking simulations [73]. Thediscovered inhibitors revealed structural diversity but

low inhibitory potency with IC50 values ranging from10 to 50 mM.

MptpA and MptpB

Tuberculosis (TB) continues to be a major cause of

morbidity and mortality throughout the world. Accordingto the World Health Organization, one-third of the

worlds population is infected with Mycobacterium tuber-

culosis [74] and about 35 million people are expected to

die from TB in the first 20 years of this century. Because

of the increasing occurrence of drug-resistant mycobac-

teria and the need of the extended use of current drugs,

new targets and drugs for therapeutic interventions are in

high demand. M. tuberculosis protein tyrosine phosphatase

A (MptpA) and MptpB are two enzymes secreted by

growing mycobacteria and believed to mediate M. tuber-

culosis survival in host macrophages by the dephosphor-

ylation of proteins that are involved in interferon

signaling, which represents a crucial pathway of the

immune system [75]. The genetic knockout of MptpB

suppressed growth of M. tuberculosis in activated macro-

phages and guinea pigs [76] and suggests that MptpA/Bcould qualify as potential drug targets in the treatment of

TB. In addition, inhibitors might also prove useful as

probe molecules in chemical biology approaches to dis-

sect the role of MptpA/B phosphatases in hostpathogen

invasion. Recently the identification of MptpA inhibitors

from screening natural-product inspired compound

libraries was reported [77]. Compound 28 is an analog

of roseophilin, a natural product found in Streptomyces

species and proved to be an inhibitor of MptpA with

an IC50 value of 0.9 mM. Utilization of fragment-based

library design resulted in the discovery of several novelclasses of MptpA inhibitors, among which compound 29

was the most active one, exhibiting a Ki value of 1.6 mM.

Additional MptpA inhibitors are based on the indolizine-

1-carbonitrile scaffold [78]. Using biology-oriented syn-

thesis (BIOS) as an efficient approach to the discovery of

new compound classes for medicinal chemistry and

chemical biology research, also inhibitors of MptpB wereidentified [60,79]. The indole derivatives 30, 31, and 32

were at least 100-fold more selective for MptpB and

displayed IC50 values in the low mM and high nM range.

Alber et al. reported the development of a potent and

selective (oxalylamino-methylene)-thiophene sulfona-

mide inhibitor for MptpB (33) (OMTS) [80

]. OMTS(33) has an IC50 value of 440 50 nM and >60-fold

specificity for MptpB over six human PTPs. The crystal

structure of MptpB in complex with OMTS revealed

substantial structural rearrangements of the enzyme, with

some residues shifting >27 A relative to the MptpB:PO4complex. In addition, extensive contacts with the cata-

lytic loop provided a potential basis for inhibitor selec-

tivity. More recently, Ellman et al. developed a substrate-

based fragment-based approach termed substrate activity

screening (SAS) to identify novel PTP inhibitors withsubmicromolar inhibitory activities [81]. Application of



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this method to MtptB resulted in the discovery of theisoxazole-based inhibitor 34. With a Ki of 220 nM com-

pound 34 is the most potent MptpB inhibitor known from

literature to date. Moreover 34 was shown to be selective

for mycobacterial (MptpA) against a panel and human

PTPs (VHR, TCPTP, CD45, and LAR). Recently, thediscovery of a new class of MptpB inhibitors was facili-

tated by the previously mentioned BIOS approach. A

stereoselective solid-phase synthesis of macroline deriva-

tives yielded 120 natural product analogs. Kinetic studies

and extensive NMR spectroscopy suggest that inhibitors

identified from these macrolines inhibit MptpB not via

the substrate-binding site, but rather via an allosteric

mechanism yet to be identified [82]. Compounds 35

and 36 selectively inhibit MptpB with IC50 values of

7.0 and 9.6 mM, respectively and did not show inhibition

of other phosphatases (MptpA, VE-PTP, PTP1B, TC-

PTPN2, and Cdc25A) up to a tested concentration of

100 mM. More recently, Terenzi et al. reported the identi-

fication of synthetic chalcones as a new class of MptpA

inhibitors [83]. Compound 37 turned out to be the most

active representative with an IC50 value of 8.4 mM.

CD45

CD45 is the first and the best characterized transmem-

brane phosphatase. It is expressed in hematopoietic cells

and plays a crucial role in T-cell receptor mediated

signaling. It regulates the phosphorylation status and

thereby activity of Src-family protein tyrosine kinases

and their substrates [84]. CD45 has gathered particular

attention because its inhibition by antibodies blocks T-

cell activation in vitro and graft rejection in mice [85].

These studies highlight the potential value of selectiveinhibitors of CD45 in the treatment of autoimmune

diseases and transplant rejection. Point mutations in

the CD45 gene have been associated with autoimmune

diseases such as multiple sclerosis [85] and autoimmune

hepatitis. In addition the negative regulation of cytokine

receptor signaling by CD45 could rationalize the loss of

CD45 activity that has been observed in several cancers,such as leukemia. CD45 has been correlated with the

proliferation of myeloma cells and could therefore be a

potential target for the treatment of multiple myelomas

[86]. In addition, recently it was reported that targeted

radiotherapy with monoclonal CD45 antibodies induces

apoptosis and breaks b-irradiation-resistance and doxor-ubicin-resistance in leukemia cells [87]. In spite of the

potential therapeutic utility of CD45-specific inhibitors,

comparatively little has been reported in the literature on

their development. The first comprehensive review on

the development of CD45 inhibitors was composed by

Lee and Burke [88]. 9,10-Phenanthrenediones (e.g. 38)

and 1,2-naphthalenediones have been reported by

researchers from AstraZeneca as potent inhibitors of

CD45 [89]. Simple structural modifications resulted in

the identification of compounds that also inhibit T-cellproliferation at low mM concentrations and are selective

for CD45 over other PTPs including PTP1B. A variety ofbenzimidazole derivatives have been identified through

high-throughput screening as potent CD45 inhibitors and

led to the development of TU-572 (39), which inhibits

CD45 with an IC50 of 0.28 mM [90]. In addition, 2-amino-

2-thioxoacetamide derivatives were also reported to inhi-bit CD45 [91]. However, the most active compound 40

exhibited only moderate activity with an IC50 of 29 mM.

ConclusionsBecause of the physiological role of phosphatases as

antagonists of kinase activity, there is a high therapeutic

potential in targeting these enzymes. Fostered by the

enthusiasm and strong indications provided by initial

PTP1B inhibitor development, the discovery of phospha-

tase-modulating agents has progressed steadily in the past

years and resulted in the generation of a variety of potent

inhibitors. However, because most of the chemical scaf-

folds that qualify as PP-inhibitors embody phosphate

mimics, several challenges remain in current phospha-

tase-related medicinal chemistry endeavors. These in-

clude limited selectivity, limited cell permeability, and

insufficient pharmacological properties. As a direct con-

sequence, only a few PP inhibitors have entered clinical

trials and new inhibitor classes are in high demand. In

addition, relatively few phosphatases are being explored

chemically and new targets may be more promising

although general limitations such as polarity of active-

site-directed inhibitors prevail. Because PPs often func-

tion in multienzyme complexes, targeting proteinprotein interactions either by stabilizers or disruptors

might offer a suitable strategy to overcome the current

limitations of small molecules directed against the activesite of the enzyme. The very recent development of short

interfering RNAs (siRNAs) for therapeutic approaches

[92,93] may be a viable new alternative in targeting

phosphatases. Interfering RNAs lead to the degradation

of messenger RNA and facilitate nucleic acids as drugsagainst otherwise challenging drug targets [94]. Recently,

Sirna Therapeutic Inc. claimed to have developed a

RNAi directed against PTP1B that potently reduces

cellular PTP1B expression levels [95]. However, at this

point only time will tell whether any of the discussed

therapeutic approaches will succeed. As soon as the first

phosphatase-targeted drug will reach the market a flood of

new development programs is to be expected just as forkinases at the end of the 1980s.

References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as:

of special interest

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