Matrix Metalloproteinase Inhibitors for Treatment of Cancer

Jerry W. Skiles, Lauren G. Monovich, and Arco Y. Jeng Novartis Institute for Biomedical Research, 556 Morris Ave., Summit, NJ 07901

Introduction Cancer is the second most common cause of death in the advanced countries; approximately one in five persons will die of this disease. It imposes great cost on society and individuals via premature disability, mortality and high treatment costs. Despite advances in the diagnosis and management of the disease and billions of dollars spent in research, only modest improvements in cure and survival rate have been realized. The primary treatment approach has relied upon cytotoxic strategies to limit tumor growth and metastasis. However, cytotoxic drugs and radiation therapy often lead to unacceptable side effects. Although the exact mechanisms responsible for the formation of the tumors and the onset of metastasis are not fully understood, the critical event signaling the initiation of the metastatic cascade in tumor invasion is thought to be the interaction of the tumor with the basement membrane. The matrix metalloproteinases (MMPs) are documented to be involved in the proteolysis of the basement membrane and other extracellular matrix (ECM) components, and they appear to play an essential role in angiogenesis, tumor growth, and metastasis. Therefore, in recent years inhibitors of the MMPs have been proposed as a possible new means of controlling tumor growth and metastasis while exhibiting a low toxicity profile compared to existing therapies. In this chapter, the biochemistry of MMPs and the rationale for treatment of cancer with MMP inhibitors are briefly reviewed. Major emphasis is on recently published, potent MMP inhibitors and their pharmacological properties. The results of clinical trials of MMP inhibitors are briefly summarized.

Overview of the MMPs Several excellent reviews on the design of MMP inhibitors have appeared (1-16). The MMPs are a family of zinc-containing, calcium-dependent enzymes involved in tissue remodelling and degradation of the ECM proteins, angiogenesis, and cell motility (17-20). Currently, 20 human MMPs are known (Table 1). The MMPs belong to the matrixin family, and they may be subdivided into five classes according to their substrate specificity, primary structures, and their cellular localization. MMP-23 is the most recently discovered MMP to be cloned and characterized (21). The enzymes are expressed as inactive zymogens which are activated by serine proteases, e.g., furin and plasmin, and other MMPs. The zymogens are excreted by a variety of connective tissue and pro-inflammatory cells, including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes. The MMPs generally consist of four distinct domains: an N-terminal pro-domain, a catalytic domain, a hinge region, and a C-terminal hemopexin-like domain. With the exception of MMP-7 and MMP-23, all human MMPs contain a conserved hemopexin-like domain. This domain is important for macromolecular substrate recognition as well as interaction with tissue inhibitors of metalloproteinases (TIMPs). The membrane-type MMPs (MT-MMPs) contain an additional transmembrane domain that anchors them in the cell surface. The activity of the MMPs is normally regulated through the presence of endogenous inhibitors such as the TIMPs. An imbalance between the MMPs and their natural inhibitors (i.e., TIMPs) is believed to be a contributing factor in the manifestation of numerous disease states involving the degradation of ECM components: osteoarthritis, rheumatoid arthritis, angiogenesis, cancer, pulmonary emphysema, corneal ulceration, atherosclerotic plaque rupturing, aortic aneurysms, and periodontal disease.

ANNUAL REPORTS IN MEDICINAL CHEMISTRY—35

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