Recent Patents on Anti-Cancer Drug Discovery - Volume 4, Issue 1, 2009

RNA interference (RNAi) is a powerful endogenous process initiated by short double stranded RNAs, which results in sequence-specific posttranscriptional gene silencing. The ability to block the expression of any disease-causing or disease-related protein emphasizes the huge therapeutic potential of this technology. In a clinical setting, however, the use of RNAi-based therapeutics is limited by their short serum half lives and poor uptake into cells. In this review, we provide an overview of recent patents in the field of short interfering RNA (siRNA) delivery and discuss recent progress in the development of efficient siRNA delivery vehicles enhancing the pharmacokinetic properties of RNAi-based therapeutics and promoting cellular uptake.

HER2 is a transmembrane tyrosine kinase receptor in the EGFR (epidermal growth factor receptor) family. The role of HER2 has been most thoroughly studied in breast cancer, in which constitutively active HER2 is overexpressed in 18-22% of cases and is correlated with a poor prognosis. Hence, effective inhibition of the constitutive HER2 signaling in cancer cells has been a major goal in the design of therapies. Therapeutic targeting of HER2 with humanized antibodies such as trastuzumab (Herceptin TM, Genentech) South San Francisco, CA) has proven to be an effective approach for the treatment of breast cancer cells that over-express HER2. The encouraging results of trastuzumab in patients with metastatic and early breast cancer diseases have prompted the evaluation of new HER2 inhibitors for increasing the potential for combinatorial therapies. This review will focus on patents that target HER2 in anti-cancer treatment.

Multi-drug resistance (MDR) is a significant barrier to effective chemotherapy of cancer. The induction of drug metabolizing enzymes (DMEs) and efflux transporters has been regarded as one of the major mechanisms of drug resistance. As a master transcription factor of DMEs and efflux transporters, pregnane X receptor (PXR), an orphan nuclear receptor known for its activation by structurally diverse compounds, is expressed in some cancer cells and tissues, and is implicated as a novel master regulator of MDR in cancers. This review describes recent publications and patents on the mechanism of PXR transcription, the expression of PXR in cancers, and its potential roles in cancer MDR. We also discuss the recent patents published to overcome PXR-mediated MDR and other potential roles of PXR in cancers.

The Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway mediates cellular responses to different growth signals and is frequently deregulated in cancer. There are three Raf kinases-A-Raf, B-Raf, and C-Raf; however, only B-Raf is frequently mutated in various cancers. The most common B-Raf mutation involves a substitution of a glutamic acid residue to a valine moiety at codon 600. Subsequently, the MAPK pathway is constitutively activated, even in the absence of any growth signals. Although early attempts to target Ras have not yielded any viable drug candidates, many novel compounds inhibiting the activities of Raf and MEK have been developed and investigated in clinical trials in recent years. The first MEK inhibitor (CI-1040) lacked efficacy in clinical trials, but its low toxicity has encouraged the search for novel compounds with enhanced target potency to inhibit MAPK activation at low nanomolar concentrations. In this review, we will discuss new patents or patent applications related to inhibitors of the Ras/Raf/MEK/ERK pathway.

Sophisticated clinical and diagnostic imaging modalities are critical for the detection, staging, treatment, and follow-up surveillance of cancer. Previously, uni- and bi-dimensional measurements of a tumor lesion were considered the “holy grail” of the assessment of tumor growth and provided imaging end-points for cytotoxic chemotherapeutic agents. With increasing understanding of cancer-related pathways and emerging discoveries of targeted signal transduction inhibitors for cancer treatment, novel pharmacodynamic endpoints of treatment efficacy are required. The innovations in medical imaging include computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single photon emission tomography (SPECT), ultrasonography (US) and, mostly in the pre-clinical arena, optical imaging. While CT and MRI provide superb anatomic resolution, physiological changes in tumor microenvironment can be assessed by dynamic contrast enhanced MRI (DCEMRI), metabolic endpoints can be established with PET and MRS protocol, and molecular biomarkers can be noninvasively followed up using PET and MRI-based molecular probes (and optical imaging mostly in pre-clinical setting). Novel protocols for improved spatial resolution, automated quantitative methods for anatomic assessment, and development of physiological, metabolic and molecular imaging probes are currently under investigation. The imaging future promises new avenues for exploration of physiological, metabolic, molecular and genetic events in the human body, performed non-invasively and in real time, using multi-modality imaging platforms. The aim of this article is to represent the available patents on imaging response assessment in oncology.

The insulin-like growth factor 1 receptor (IGF-1R) and its associated signalling system has provoked considerable interest over recent years as a novel therapeutic target in cancer. A brief outline of the IGF-1R signalling system and the rationale for its use in cancer medicine is given. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417, NVPAEW541, NVP-ADW742, AG1024, potent quinolinyl-derived imidazo (1,5-a)pyrazine PQIP, picropodophyllin PPP, Nordihydroguaiaretic acid Insm-18/NDGA). The following tumour types are specifically discussed: lung, breast, colorectal, pancreatic, NETs, sarcoma, prostate, leukaemia, multiple myeloma. Other tumour types are mentioned briefly: squamous cell carcinoma of the head and neck, melanoma, glioblastoma, ovary, gastric and mesothelioma. Results of early stage clinical trials, involving recently patented drugs. are included where appropriate. We then outline the current understanding of toxicity related to IGF-1R targeted therapy, and finally outline areas for further research.

Aberrations in the Ubiquitin-Proteasome System (UPS) have been recently connected to the pathogenesis of several human protein degradation disorders (e.g., cancer and neurodegenerative diseases), so that proteasome is now considered an important target for drug discovery. Small molecules able to inhibit and modulate UPS have been, in fact, described as novel tools for a new approach in anti-cancer therapy. In particular Proteasome Inhibitors (PIs), blocking activation of nuclear factor-kappa B (NF-kB), trigger a decreased cellular proliferation and angiogenic cytokine production, induce cell death and inhibit tumor cell adhesion to stroma. Furthermore, several studies have demonstrated that PIs potentiate the activity of other anti-cancer treatment, in part by down-regulating chemoresistance pathways. Therefore pharmacologic, preclinical, and clinical data suggested the use of PIs in anticancer strategies, for their potential therapeutic relevance in the treatment of cancer and inflammatory-related diseases. This review focuses on recent advances in the development of PIs anticancer agents highlighting both novel patented compounds and novel therapeutic protocol of intervention.

The setup of tumorigenesis processes is generally associated with various events leading to abnormal expression of oncogenes and/or tumor suppressor genes. Recently, the expression and/or activity of a range of molecules involved in these processes were reported to require proteolytic processing of their precursor proteins by the serine proprotein convertases (PCs) in order to mediate their biological functions. These include adhesion molecules, proteases, growth factors, cytokines and their receptors. Since their discovery, the identification of new PCs substrates and specific PCs inhibitors became an attractive strategy in cancer therapy. In this review, we will report the implication of these enzymes and the processing of their substrates in tumor progression and metastasis. Newly reported studies on the potential use of the PCs as new therapeutic targets will be also discussed.

Noscapine is an isoqiunoline alkaloid found in opium latex. Unlike most other alkaloids obtained from opium latex, noscapine is not sedative and has been used as antitussive drug in various countries. Recently, it has been introduced as an anti-mitotic agent. This drug can be used orally .When the resistance to other anti-cancer drugs such as paclitaxel menifests, noscapine might be effective. Therefore, noscapine and its analogs have great potential as novel anticancer agents.

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