Recent Patents on Anti-Cancer Drug Discovery - Volume 5, Issue 2, 2010

Vacuolar-type ATPases are multicomponent proton pumps involved in the acidification of single membrane intracellular compartments such as endosomes and lysosomes. They couple the hydrolysis of ATP to the translocation of one to two protons across the membrane. Acidification of the lumen of single membrane organelles is a necessary factor for the correct traffic of membranes and cargo to and from the different internal compartments of a cell. Also, V-ATPases are involved in regulation of pH at the cytosol and, possibly, extracellular milieu. The inhibition of V-ATPases has been shown to induce apoptosis and cell cycle arrest in tumour cells and, therefore, chemicals that behave as inhibitors of this kind of proton pumps have been proposed as putative treatment agents against cancer and many have been patented as such. The compounds filed in patents fall into five major types: plecomacrolides, benzolactone enamides, archazolids, chondropsins and indoles. All these have proved to be apoptosis inducers in cell culture and many to be able to reduce xenograft tumor growth in murine models. The present review will summarize their general structure, origin and mechanisms of action and put them in relation to the patents registered so far for the treatment of cancer.

Cell penetrating peptides (CPPs) are 9-35mer cationic and/or amphipathic peptides that are rapidly internalized across cell membranes. Importantly, they can be linked to a variety of cargo, including anti-cancer therapeutics, making CPPs an efficient, effective and non-toxic mechanism for drug delivery. In this review, we discuss a number of CPP conjugated therapies (CTTs) that are either patented are in the progress of patenting, and show strong promise for clinical efficacy. The CTTs discussed here target a number of different processes specific to cancer progression, including proliferation, survival and migration. In addition, many of these CTTs also increase sensitivity to current anti-cancer therapy modalities, including radiation and other DNA damaging chemotherapies, thereby decreasing the toxic dosage required for effective treatment. Mechanistically, these CTTs function in a dominant-negative manner by blocking tumorspecific protein-protein interactions with the CPP-conjugated peptide or protein. The treatment of both cell lines and mouse models demonstrates that this method of molecular targeting results in equal if not greater efficacy than current standards of care, including DNA damaging agents and topoisomerase inhibitors. For the treatment of invasive carcinoma, these CTTs have significant clinical potential to deliver highly targeted therapies without sacrificing the patient's quality of life.

Matrix metalloproteinases (MMPs) belong to a family of closely related calcium- and zinc-dependent endopeptidases involved in the degradation and remodeling of extracellular matrix (ECM) proteins that are associated with the tumorigenic processes. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function. Thus, MMP inhibitors (MMPIs) are expected to be useful chemotherapeutic agents for the treatment of malignant cancer, osteoarthritis, and rheumatoid arthritis. A vast number of small molecular MMPIs have been developed in recent years. Although there have been considerable preclinical and clinical studies on these inhibitors, most of the effective candidates in clinical trials, however, have yielded unsatisfactory results, thus they are as yet unavailable for use as therapeutic drugs. Currently, more efforts have been directed to the design of specific inhibitors towards certain MMP family members for selective usage. This review will focus primarily on an analysis of recent developed MMPIs that have entered preclinical or clinical trials, and recently registered patents with regard to new highly selective MMPIs in USA or patent applications related to the specific inhibitors of MMPs. We also analyze the clinical failure and discuss the possible strategies to best optimize the development of these novel agents.

Targeting the epidermal growth factor receptor (EGFR), an important component in carcinogenesis, is an attractive therapeutic option for selective anticancer therapy. Several EGFR inhibitors, mostly monoclonal antibodies and tyrosine kinase inhibitors are under investigation in the treatment of colorectal cancer. Although there has been some progress in the treatment of colorectal cancer with combination chemotherapy, the repertoire of active agents is still limited. More recently the anti-EGFR drugs cetuximab and panitumumab have made an impact in the treatment of metastatic disease but with variable response rates. Although the appearance of a skin rash confers a higher response rate, immunohistochemical staining of EGFR at baseline does not. Several studies have now focused on identifying predictive biological markers at a molecular level. Exciting data has demonstrated KRAS mutation status to be the first predictive marker of response to anti-EGFR monoclonal antibodies (mAbs) and has led a new era in the development of targeted therapies in colorectal malignant disease. The aim of this review is to evaluate the impact of anti-EGFR therapies in the treatment of metastatic colorectal cancer; and to present the current data on predictive markers including KRAS status, PTEN expression and germinal gene polymorphisms. The relevant patents are discussed.

Flavonoids belong to polyphenolic secondary metabolites with broad-spectrum pharmacological activities and extensive biological effects, and the most prominent activity is their potential role as anticancer agents. In recent years, flavonoids and their synthetic analogues have been intensely investigated in the treatment of ovarian, breast, cervical, pancreatic, and prostate cancer. To some extent, chemical structures of flavonoids will influence their anticancer activities. Thus, some new analogues based on the structural skeleton of these flavonoids have been synthesized and investigated. This review presents recent advances on the patents concerning of the natural flavonoids and their synthetic analogues in the treatment of cancers, and new synthetic approaches and possible structure-activity relationships of flavonoids are also briefly summarized.

A big challenge for research today is the manipulation of the immune system in order to destroy the neoplastic cells of tumors different origins by using cytokines and other immunostimulants. Interferon-alpha (IFN-α) has been used clinically and has been shown to inhibit the proliferation of various cell types in vivo and in vitro. This cytokine has been widely used in the treatment of infectious and chronic degenerative diseases and cancer. In this review, we describe different patents covering the use of cytokines and peptides as therapies for cervical intraepithelial neoplasias and cervical cancer, paying special attention to the use of IFN-α.

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