Molecular targets in the discovery and development of novel antimetastatic agents: Current progress and future prospects

Abstract

Tumour invasion and metastasis have been recognized as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors and multiple signalling pathways. The present review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets used in the discovery of antimetastatic agents. Several promising targets have been highlighted, including receptor tyrosine kinases, effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator, adhesion molecules and their receptors, signalling pathways (e.g. phosphatidylinositol 3-kinase, phospholipase Cγ1, mitogen-activated protein kinases, c-Src kinase, c-Met kinases and heat shock protein. The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that have shown remarkable clinical outcome are anti-angiogenic agents (e.g. bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and are yet to have their clinical efficacy proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs; e.g. marimastat) and more selective versions of them (e.g. prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects that led to the premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis.

Targeting midkine and pleiotrophin signalling pathways in addiction and neurodegenerative disorders: recent progress and perspectives

“…Disruption of this balance underlies different diseases (Hendriks et al ., ). For this reason, PTPs (including the receptor‐like class) are currently being considered as prime targets for drug design (Wong et al ., ) following the path opened by selective PTK inhibitors that were previously developed and reached clinical use (Ventura and Nebreda, ). Pharmaceutical development of therapeutics targeting PTPs has been proposed to treat a wide variety of diseases including diabetes mellitus, neural diseases such as PD and Alzheimer's disease, inflammatory diseases and allergy (Herradon and Ezquerra, ; Heneberg, ).…”

Synthesis of Amino Acid‐comprising Sialyltransferase Inhibitors and Their Antimetastatic Activities against Human Breast Cancer Cells

“…Thus reaction of Fmoc-Ser(OTBDPS)-OH with 24 followed by treatment with tetrabutylammonium fluoride (n-Bu 4 NF) afforded the amino alcohol which could be subsequently converted to 4 using a similar deprotection procedure. To prepare the D-form Glu-LCA 7, esterification of the secondary alcohol 24 using Boc-D-Glu(OAll)-OH was followed by liberation of the d-carboxylic acid of D-Glu with Pd(PPh 3 ) 4 in the presence of morpholine and subsequent removal of tBu and Boc groups.…”

“…However, study about the antimetastatic agents is very rare and limited. 4 Hypersialylation at the non-reducing end of glycoproteins or glycolipids plays an important role in cellular interactions such as cell-cell adhesion, tumor cell metastasis and invasions. 5 Modifications of sialylation in vivo are mediated and regulated by various glycoprotein-and glycolipid-specific sialyltransferases (STs).…”

Copy Number Networks to Guide Combinatorial Therapy of Cancer and Proliferative Disorders

“…CDA is inhibited by chemotherapeutic drugs such as tetrahydrouridine (Beumer et al, 2008) and zebularine (Lemaire et al, 2009). MMP16 is inhibited by marimastat (Wong et al, 2013). Both CDA (interactors FDR < 10 -4 ) and MMP16 (interactors FDR < 10 -5 ) were linked with a number of additional genes whose products can be antagonized by available drugs (Figure 3).…”

“…One potential example of this synergistic strategy is provided by marimastat, which inhibits MMP16 in the RH pathway terminating on EGFR (Figure 3). Marimastat is not used clinically because of an unacceptable side effect profile (Wong et al, 2013). By combining marimastat at low concentrations with other drugs in a network guided strategy, it might be possible to maximize their common therapeutic effects, while minimizing the divergent adverse effects.…”