Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 15, Number 20, 2009

Contents

ADAMs: Targets for Drug Discovery
Executive Editor: Marcia L. Moss


Editorial: Pp. 2270-2271


ADAM8/MS2/CD156, an Emerging Drug Target in the Treatment of Inflammatory and Invasive Pathologies Pp. 2272-2281
G. Koller, U. Schlomann, P. Golfi, T. Ferdous, S. Naus and J.W. Bartsch
[Abstract] [Purchase Article] [PMID: 19601829 PubMed - indexed for MEDLINE]


ADAM9 as a Potential Target Molecule in Cancer Pp. 2282-2287
L. Peduto
[Abstract] [Purchase Article] [PMID: 19601830 PubMed - indexed for MEDLINE]


ADAM10 as a Therapeutic Target for Cancer and Inflammation Pp. 2288-2299
H.C. Crawford, P.J. Dempsey, G. Brown, L. Adam and M.L. Moss
[Abstract] [Purchase Article] [PMID: 19601831 PubMed - indexed for MEDLINE]


Targeting ADAM12 in Human Disease: Head, Body or Tail? Pp. 2300-2310
J. Jacobsen and U.M. Wewer
[Abstract] [Purchase Article] [PMID: 19601832 PubMed - indexed for MEDLINE]


The Therapeutic Potential of ADAM15 Pp. 2311-2318
N. Lucas, A.J. Najy and M.L. Day
[Abstract] [Purchase Article] [PMID: 19601833 PubMed - indexed for MEDLINE]


ADAM17 as a Therapeutic Target in Multiple Diseases Pp. 2319-2335
J. Arribas and C. Esselens
[Abstract] [Purchase Article] [PMID: 19601834 PubMed - indexed for MEDLINE]


ADAM19/Adamalysin 19 Structure, Function, and Role as a Putative Target in Tumors and Inflammatory Diseases Pp. 2336-2348
B. Qi, R.G. Newcomer and Q.-X.A. Sang
[Abstract] [Purchase Article] [PMID: 19601835 PubMed - indexed for MEDLINE]


ADAM28 as a Target for Human Cancers Pp. 2349-2358
S. Mochizuki and Y. Okada
[Abstract] [Purchase Article] [PMID: 19601836 PubMed - indexed for MEDLINE]


A Review of the ADAMTS Family, Pharmaceutical Targets of the Future Pp. 2359-2374
M.D. Tortorella, F. Malfait, R.A. Barve, H.-S. Shieh and A.-M. Malfait
[Abstract] [Purchase Article] [PMID: 19601837 PubMed - indexed for MEDLINE]




Abstracts


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Editorial: ADAMs: Targets for Drug Discovery

From cancer to obesity to bacterial infections, dysregulation of metalloproteinases, can be a causative factor in disease states. A subclass of metalloproteinases, the metzincins, defines a super family that is involved in a number of pathophysiological conditions. Each member contains a HEXGHXXGXXHD region that coordinates the active site zinc atom and is critical for catalysis. In addition, they also have a structural motif downstream from the coordination site, beginning with a methionine residue that is known as the met turn.

Early on, much promise was given to the metzincin family members, the matrixins. The matrixins are a family composed of matrix metalloproteinases (MMPs) that are important for extracellular matrix turnover, and are also capable of driving progression of diseases such as cancer and arthritis. At approximately the same time as MMPs were falling out of favor due to unwanted side effects associated with their inhibition, a new family was added to the metzincins metalloproteinases; the adamalysins. The first in the adamalysin family, ADAM1, was discovered by Carl Blobel in Judith White’s laboratory at the University of Virginia. ADAM1, also named Fertilin, was found to be important for sperm/egg fusion. Since then a total of 25 ADAMs have been uncovered by cloning and/or sequencing of the human genome. ADAM family members now make up the majority of pharmaceutical targets currently undergoing preclinical and clinical evaluation.

The ADAM family was expanded in 1997 to include the ADAMTS proteins, which are ADAMs with thrombospondin motifs. Kuno et al. reported the gene sequence encoding a proteinase that was upregulated in tumors, which was named ADAMTS-1. Shortly after this discovery, when pharmaceutical companies were actively searching for the enzyme(s) responsible for promoting osteoarthritis by the degradation of aggrecan, ADMP-1 and ADMP-2 were found by a group led by Elizabeth Arner while at Dupont Merck, and these were subsequently renamed ADAMTS-4 and 5. There are currently 19 ADAMTS family members.

The ADAM and ADAMTS families of proteins are the topics of this Current Pharmaceutical Design edition. Of the 25 human ADAM family members, only 13 are active metalloproteinases, and 8 were chosen for review: ADAM8, 9, 10, 12, 15, 17, 19 and 28. In addition a single comprehensive review on all the ADAMTS proteins is provided.

ADAM8, also known as MS2 or CD156 was cloned from a murine macrophage cDNA library by the group of Shunsuke Yamamoto of Japan. The protein was originally characterized as a monocyte specific cell surface antigen. More recently, a number of novel ADAM8 substrates were defined. ADAM8 has been found to be overexpressed in the inflamed CNS, in asthmatic lungs, in bone destruction, and in highly invasive types of cancer. In Koller et al. [1], the current knowledge about the role of ADAM8 in these disease states will be discussed.

ADAM9 was initially discovered by a group led by Atsuku Fujisawa-Sehara of Japan in 1995. Shortly thereafter, ADAM9 was cloned by Carl Blobel’s laboratory and knock out mice were made and characterized. In his paper, Peduto [2] states that these mice show no overt phenotype. However, when tested in a prostate tumor model, tumors from the knock out mice are more differentiated than those from wild type animals, lending credence to the hypothesis that ADAM9 overexpression can drive certain forms of cancer.

ADAM10 is also implicated in promoting carcinogenesis when dysregulated. However, early on, ADAM10 was purified and cloned by Paul Glynn’s group, and they suspected that the proteinase was responsible for some of the damage in the CNS due to multiple sclerosis (MS). ADAM10 is highly expressed in the brain, and could play a role in diseases such as MS, but it has confirmed roles in regulated intramembrane proteolysis (RIP) as an alpha secretase for amyloid precursor protein.(APP), CD44, and Notch. Crawford et al. [3] describes RIP as a process whereby extracellular domains are cleaved in consecutive steps by alpha secretases such as ADAM10, followed by a presenilin dependent gamma secretase activity that generates intracellular domain (ICDs). The ICDs are able to translocate to the nucleus where they regulate transcription of a variety of genes. Currently over 40 substrates have been identified for ADAM10, but only a handful are involved in RIP. In addition to playing a role in the CNS, ADAM10 is clearly involved in cancer progression because of its ability not only to shed Notch and CD44, but also to process the EGF ligands, EGF, HB-EGF, betacellulin, and the HER2 receptor. Likewise, ADAM10 is a principal sheddase for CD23, and chemokines, CXCL16 and CX3CL1, suggesting that it also plays a central role in inflammatory diseases.

ADAM12, cloned at the same time as ADAM9 in Atsuku Fujisawa-Sehara’s group, also processes some EGF ligands and is suggested to be involved in cellular proliferation. Jacobsen et al. [4] describes ADAM12 as composed of head, body, and tail, with each segment having attributes that implicate the proteinase in cancer, inflammation, obesity, and cardiovascular disease. ADAM12 deficient mice are leaner than their wild type littermates, implicating ADAM12 in metabolic regulating events. Furthermore, in a breast carcinoma model, the knock out mice have more tumors, indicating that removing ADAM12 could promote cancer. High levels of both the soluble and membrane bound forms of ADAM12 have been observed in several types of carcinomas, suggesting that ADAM12 is involved in tumor cell proliferation.

ADAM15 knock out mice have also been described. Lucas et al. [5], discusses how ADAM15 may play a protective role in arthritis since ADAM15 deficient mice exhibit a higher occurrence of symptoms associated with RA, for example, hyperplasia and tissue destruction. In diseases such as prostate cancer, knockdown of ADAM15 reduced metastatic spread of cells in vivo and inhibited or reversed a number of malignant processes. In addition, using protein arrays, it wsa discovered that ADAM15 levels were upregulated in prostate and breast cancer tissues compared to benign controls. These findings suggest that ADAM15 does function in pathophysiologies such as tumor progression and metastasis.

Unlike ADAM15, ADAM17 is well characterized in terms of substrate usage and its importance in disease states. Two groups, led by Roy Black of Immunex (now Amgen) and Marcia Moss while at Glaxo, independently verified that ADAM17 was a tumor necrosis factor-alpha converting enzyme and this discovery suggested that ADAMs in general were processing enzymes for type I and II integral membrane proteins. Since this time, Arribas and Esselens describe close to 50 substrates for ADAM17 [6]. In their review, they discuss how ADAM17 is a principal player in cancer, inflammation, metabolic and renal disease because of its ability to process a diverse set of substrates such as TNF-alpha and ErbB ligand family members, amphiregulin, transforming growth factor-alpha, epiregulin, and heregulin. Like ADAM10, ADAM17 also participates in RIP, where it utilizes such substrates as APP, CD44, and IL1-IIR. Because of its unusual number of substrates, there can be side effects of treatments targeting ADAM17. Therefore, companies are beginning to use ADAM17 inhibitors for cancer, rather than for inflammatory diseases such as rheumatoid arthritis.

Less is known about ADAM19 and ADAM28. However in Qi et al. [7] and Mochizuki and Okada [8], these two ADAMs are discussed in terms of their relevance to cancer. ADAM19, for example, like ADAM17, can process heregulins. The shedding of neuregulin-β1 by ADAM19 could activate ErbB2/ErbB3 receptors in an autocrine fashion and ErbB2 has been detected in highly malignant gliomas. ADAM19 is markedly upregulated in various abnormal renal cell types when compared to normal human kidneys and a study found ADAM19 co-localized with tubular and interstitial neuregulin. ADAM28, in both membrane bound and soluble forms, is also overexpressed in carcinomas.

Finally, Totorella et al. [9] provides a comprehensive review of the ADAMTS family of metalloproteinases. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their altered regulation has been implicated in diseases such as cancer, arthritis, and atherosclerosis. The recent elucidation of crystal structures for ADAMTS-1, -4, and -5 will allow for the design of potent and selective small molecule inhibitors that will hopefully lead to novel drug candidates in the near future.

References

[1] Koller G, Schlomann U, Golfi P, Ferdous T, Naus S, Bartsch JW. ADAM8/MS2/CD156, an emerging drug target in the treatment of inflammatory and invasive pathologies. Curr Pharm Des 2009; 15(20): 2272-2281.

[2] Peduto L. ADAM9 as a potential target molecule in cancer. Curr Pharm Des 2009; 15(20): 2282-2287.

[3] Crawford H, Dempsey PJ, Brown G, Adam L, Moss ML. ADAM10 as a therapeutic target for cancer and inflammation. Curr Pharm Des 2009; 15(20): 2288-2299.

[4] Jacobsen J, Wewer UM. Targeting ADAM12 in human disease: head, body or tail? Curr Pharm Des 2009; 15(20): 2300-2310.

[5] Lucas N, Najy AJ, Day ML. The therapeutic potential of ADAM15. Curr Pharm Des 2009; 15(20): 2311-2318.

[6] Arribas J, Esselens C. ADAM17 as a therapeutic target in multiple diseases. Curr Pharm Des 2009; 15(20): 2319-2335.

[7] Qi B, Newcomer RJ, Sang Q-XA. ADAM19/adamalysin 19 structure, function, and role as a putative target in tumors and inflammatory diseases. Curr Pharm Des 2009; 15(20): 2336-2348.

[8] Mochizuki S, Okada Y. ADAM28 as a target for human cancers. Curr Pharm Des 2009; 15(20): 2349-2358.

[9] Tortorella MD, Malfait F, Barve RA, Shieh H-S, Malfait A-M. A review of the ADAMTS family, pharmaceutical targets of the future. Curr Pharm Des 2009; 15(20): 2359-2374.


Marcia L. Moss
BioZyme, Inc.
1513 Old White Oak Church Rd.
Apex, NC 27523
USA
E-mail: mmoss@biozyme-inc.com


[Back to top] [Purchase Article] [PMID: 19601829 PubMed - indexed for MEDLINE]
ADAM8/MS2/CD156, an Emerging Drug Target in the Treatment of Inflammatory and Invasive Pathologies
G. Koller, U. Schlomann, P. Golfi, T. Ferdous, S. Naus and J.W. Bartsch

While it is highly accepted that ADAM family members with ubiquitous expression patterns, such as ADAM10 and ADAM17 have major roles in homoeostasis and pathology, ADAM8 was initially considered as an immune-specific ADAM with a cell-specific expression pattern. Therefore, ADAM8 had a “sleeping beauty” existence for many years, and has recently come back into focus as it was detected under several pathological conditions. These were found to typically involve inflammation and remodelling of the extracellular matrix, including cancers and serious respiratory diseases such as asthma. In these diseases, induced expression of ADAM8 by different stimuli results in cleavage of various substrates, including cell adhesion molecules, cytokine receptors, and ECM components. Involvement of ADAM8 in individual diseases indicates its usefulness as both a diagnostic and prognostic marker. Even more strikingly, as ADAM8 progressively emerges as a key effector in pathological processes, so does its attractiveness as a therapeutic target rather than being a mere indicator of disease and its progression. This is encouraged by analysis of ADAM8 null mice, identifying no adverse phenotype in the absence of functional ADAM8. Thus, ADAM8 potentially is an attractive drug target in a variety of diseases. In this review, the current knowledge on ADAM8 in diseases and avenues for specific inhibition based on unique biochemical features of ADAM8 will be presented.


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ADAM9 as a Potential Target Molecule in Cancer
L. Peduto

ADAM (a disintegrin and metalloproteinase) proteins have a predominant role in the protein ectodomain shedding of membrane-bound molecules. ADAMs have emerged as critical regulators of cell-cell signaling during development and homeostasis, and are believed to contribute to pathologies, such as cancer, where their regulation is altered. ADAM9 is consistently overexpressed in various human cancers, and plays a role in tumorigenesis in mouse models. ADAM9 cleaves and releases a number of molecules with important roles in tumorigenesis and angiogenesis, such as EGF, FGFR2iiib, Tie-2, Flk-1, EphB4, CD40, VCAM-1, and VE-cadherin, and could represent a potential therapeutic target in tumors where it is highly expressed. This review provides an overview of ADAM9 with a major focus on its contribution to tumorigenesis. Its role in the shedding of cell surface molecules will be discussed along with emerging aspects of regulation and possible functions in cancer development.


[Back to top] [Purchase Article] [PMID: 19601831 PubMed - indexed for MEDLINE]
ADAM10 as a Therapeutic Target for Cancer and Inflammation
H.C. Crawford, P.J. Dempsey, G. Brown, L. Adam and M.L. Moss

Both cancer and chronic inflammatory diseases are often marked by homeostatic signal transduction pathways run amok. Cleavage of membrane-bound substrates by extracellular metalloproteinases is frequently the rate limiting step in activating many of these pathways, resulting either in liberation of active ligands (shedding) or initiating further processing into bioactive cytoplasmic domains (regulated intramembrane proteolysis or RIP). ADAM10 is a member of the ADAM (A Disintegrin And Metalloproteinase) family of transmembrane metalloproteinases implicated in the RIPing and shedding of dozens of substrates that drive cancer progression and inflammatory disease, including Notch, E-cadherin, EGF, ErbB2 and inflammatory cytokines. ADAM10’s emerging role as a significant contributor to these pathologies has led to intense interest in it as a potential drug target for disease treatment. Here we discuss some of the established functions of ADAM10 and the implications of its inhibition in disease progression.


[Back to top] [Purchase Article] [PMID: 19601832 PubMed - indexed for MEDLINE]
Targeting ADAM12 in Human Disease: Head, Body or Tail?
J. Jacobsen and U.M. Wewer

ADAM12/meltrin a is a type I transmembrane multidomain protein involved in tumor progression and other severe diseases, including osteoarthritis, and as such could be considered as a potential drug target. In addition to protease activity, ADAM12 possesses cell binding and cell signaling properties. This functional trinity is reflected in the structure of ADAM12, which can be divided into head, body, and tail. The head of the protein (consisting of the pro and catalytic domains) mediates processing of growth factors and cytokines and has been implicated in epidermal growth factor (EGF) and insulin-like growth factor receptor signaling. The body of the protein (consisting of the disintegrin, cysteine-rich, and EGF-like domains) is involved in contacts with the extracellular matrix and other cells through interactions with integrins and syndecans. Finally, the tail of the protein (consisting of the cytoplasmic domain) is engaged in interactions with intracellular signaling molecules. In many studies, ADAM12 overexpression has been correlated with disease, and ADAM12 has been shown to promote tumor growth and progression in cancer. On the other hand, protective effects of ADAM12 in disease have also been reported. Future investigations should address the precise mechanisms of ADAM12 in disease and biology in order to counterbalance the benefits from targeting ADAM12 therapeutically with possible side effects. This review describes the biology of ADAM12, its association with disease, and evaluates the possible approaches to targeting ADAM12 in human disease.


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The Therapeutic Potential of ADAM15
N. Lucas, A.J. Najy and M.L. Day

ADAM15 is a widely expressed multi-domain protease that has been implicated in the pathogenesis of many human diseases. Given the diversity of the ADAM15 functional domains, this protease is thought to affect several important cellular processes, including cell adhesion, degradation of extracellular matrix components, and ectodomain shedding of membrane-bound growth factors that are intrinsic to cancer and various inflammatory conditions. The multiple levels by which the activity of ADAM15 can be regulated include signal transduction, modulation of catalytic function, spatial regulation, and post-translational modifications. Taken together, this multi-functional disintegrin protease not only offers a variety of potential targets for therapeutic intervention, but also represents an attractive target for pharmaceutical consideration due to its involvement in key cellular processes and various disease states. Modalities aimed at inhibiting protease activation, metalloproteinase activity, or integrin binding capability could prove beneficial for the treatment of cancer and inflammatory diseases.


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ADAM17 as a Therapeutic Target in Multiple Diseases
J. Arribas and C. Esselens

As a metalloproteinase specialized in releasing membrane-tethered proteins, A Disintegrin and A Metalloproteinase 17 (ADAM17), also known as Tumor necrosis factor-α Converting Enzyme (TACE) or less commonly CD156q, has received more than its share of attention. This is mainly because major contemporary pathologies like cancer, inflammatory and vascular diseases seem to be connected to its cleavage abilities. The involvement in such a broad spectrum of diseases is due to the large variety of substrates that ADAM17 is able to cut. ADAM17 can activate growth factors or inactivate receptors by shedding their extracellular domain from the cell membrane. Similarly, it can detach cells by cleaving cell adhesion molecules. Some of these proteolytic events are part of cleavage cascades known as Regulated Intramembrane Proteolysis and lead to intracellular signaling. It is therefore clear that ADAM17 literally fulfills a key role in diverse processes and pathologies, making it a prime target for developing therapies. Here we review the role of ADAM17 in health and disease and highlight the problems to overcome for ADAM17 to mature towards a therapeutically valuable target.


[Back to top] [Purchase Article] [PMID: 19601835 PubMed - indexed for MEDLINE]
ADAM19/Adamalysin 19 Structure, Function, and Role as a Putative Target in Tumors and Inflammatory Diseases
B. Qi, R.G. Newcomer and Q.-X.A. Sang

A disintegrin and metalloproteinase 19 (ADAM19, or adamalysin 19) is a cell surface glycoprotein with a signal sequence, a prodomain, a metalloproteinase domain, a disintegrin domain, a cysteine-rich domain, a epidermal growth factor-like domain, a transmembrane domain, and a cytoplasmic domain. It is an endopeptidase that cleaves extracellular matrix proteins and sheds growth factors and cytokines such as neuregulins, heparin-binding epidermal growth factor, tumor necrosis factor (TNF)-α, and TNF-related activation-induced cytokine. The ADAM19 gene was cloned from human, monkey, and mouse. It is expressed in multiple organs and tissues including heart, lung, bones, brain, spleen, liver, skeletal muscle, kidney, and testes. ADAM19 plays essential roles in embryo implantation, cardiovascular morphogenesis, neurogenesis, and other developmental processes. It has constitutive α-secretase activity associated with processing Alzheimer’s disease amyloid precursor protein (APP) to non-amyloidogenic fragments; thus, it is neuroprotective. Those observations indicate that inhibition of ADAM19 activity is undesirable during embryo development and morphogenesis, and during the development of Alzheimer’s disease. On the contrary, in adults, ADAM19 is upregulated in human brain tumors such as astrocytoma and glioblastoma and is correlated with the invasiveness of glioma. It is also over-expressed by many human cancerous cell lines including cancers of the colon, ovary, lung, and brain. Abnormally high expression of ADAM19 is also linked to inflammation and fibrosis of the lung and kidney. Targeted inhibition of ADAM19 may be crucial for the treatment of certain types of tumors and inflammatory diseases.


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ADAM28 as a Target for Human Cancers
S. Mochizuki and Y. Okada

ADAM28 is a member of the ADAM (a disintegrin and metalloproteinase) gene family and consists of two isoforms, prototype membrane-type form and short secreted form. The metalloproteinase domain of ADAM28 has the zinc-binding consensus sequence, and ADAM28 exhibits catalytic activity to a few substrates such as insulin-like growth factor binding protein-3. The disintegrin domain interacts with integrins α4β1, α4β7 and α9β1. In human non-small cell lung carcinomas and breast carcinomas, ADAM28 is overexpressed predominantly by carcinoma cells, and the expression correlates with carcinoma cell proliferation and lymph node metastasis. In this review we present our data on the activation of proADAM28, the tissue localization in human cancers and the interaction molecules, and discuss the regulation of ADAM28 activity and gene expression, the functions of ADAM28 in human cancers and the possibility of ADAM28 as a target for cancers.


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A Review of the ADAMTS Family, Pharmaceutical Targets of the Future
M.D. Tortorella, F. Malfait, R.A. Barve, H.-S. Shieh and A.-M. Malfait

The a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of metalloproteases consists of 19 members. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their altered regulation has been implicated in diseases such as cancer, arthritis and atherosclerosis. Unlike other metalloproteinases, ADAMTS members demonstrate a narrow substrate specificity due to the various exosites located in the C-terminal regions of the enzymes, which influence protein recognition and matrix localization. The tight substrate specificity exhibited by ADAMTS enzymes makes them potentially safe pharmaceutical targets, as selective inhibitors designed for each member will result in the inhibition or cleavage of only a limited number of proteins. With the recent elucidation of crystal structures for ADAMTS-1, -4 and -5, the design of potent and selective small molecule inhibitors is underway and will lead to drug candidates for evaluation in clinical trials in the next 5-10 years.