Recent Patents on Anti-Cancer Drug Discovery - Volume 12, Issue 3, 2017

Background: Alteration of cellular metabolism is a hallmark of cancer, which underlies exciting opportunities to develop effective, anti-cancer therapeutics through inhibition of cancer metabolism. Nicotinamide Adenine Dinucleotide (NAD+), an essential coenzyme of energy metabolism and a signaling molecule linking cellular energy status to a spectrum of molecular regulation, has been shown to be in high demand in a variety of cancer cells. Depletion of NAD+ by inhibition of its key biosynthetic enzymes has become an attractive strategy to target cancer. Objective and Method: The main objective of this article is to review the recent patents which develop and implicate the chemical inhibitors of the key NAD+ biosynthetic enzymes for cancer treatment. We first discuss the biological principles of NAD+ metabolism in normal and malignant cells, with a focus on the feasibility of selectively targeting cancer cells by pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT) and indoleamine/tryptophan 2,3-dioxygenases (IDO/TDO), the rate-limiting salvage and de novo NAD+ biosynthetic enzymes, respectively. We then analyze a series of recent patents on development and optimization of chemical scaffolds for inhibiting NAMPT or IDO/TDO enzymes as potential anticancer drugs. Conclusion and Results: We have reviewed 16 relevant patents published since 2015, and summarized the chemical properties, mechanisms of action and proposed applications of the patented compounds. Without a better understanding of the properties of these compounds, their utility for further optimization and clinical use is unknown. For the compounds that have been tested using cell and mouse models of cancer, results look promising and clinical trials are currently ongoing to see if these results translate to improved cancer treatments.

Background: Poly (ADP-ribosyl) polymerase 1 (PARP1) is important in maintaining genomic stability, repairing DNA damage, and regulating transcriptional processes. Altered PARP1 activity is associated with a multitude of pathologies especially cancer. The broad application prospects of PARP1 inhibitors attract many well-known pharmaceutical companies, which promotes the development of PARP1 inhibitors. Objective: Present review aims to introduce PARP1 inhibitors by their structures and try to point out future development direction of PARP1 inhibitors. Method: Details regarding the PARP1and PARP1 inhibitors are obtained from PubMed literatures and patent databases. Conclusion: The action mode of PARP1 inhibitors developed so far is competing with NAD+ for the catalytic site of PARP1. Using such inhibitors affects multiple NAD+-dependent enzymatic pathways, which results in secondary toxic effects. Designing inhibitors targeting other binding sites on the PARP1 protein is a strategy to bypass this pitfall. Analyzing the structure-activity relationships of active PARP1 inhibitors described in the patents, we conclude that for the binding activity, amide group, aromatic ring or heterocyclic ring with rich electronics and heteroatom-substituted in the meta position of amide group are essential. Big substituents introduced in the heterocyclic ring can enhance inhibitory activity and improve solubility or other physicochemical properties. Clinical trials of PARP1 inhibitor were focused on cancer therapies and have achieved remarkable results.

Background: Bone metastasis is a common complication of certain types of cancer, and unfortunately, it is still incurable to date. Immune system is a major defence against tumor cells and bone metastasis. However, the immunodeficient mouse models are widely used in most researches of bone metastasis, thereby excluding the regulatory roles of the immune system in bone metastasis. Objective: The aim was to provide a comprehensive overview on the cellular and molecular mechanisms by which immune cells interact with tumor cells and bone cells, as well as recent related patents. Method: We performed a literature search of PubMed database for the current knowledge on the interaction between bone metastasis and immune system. Recent related patents were obtained from World Intellectual Property Organization (WIPO) website. Results: Immune cells in the bone-tumor microenvironment include dentritic cells, monocytes/ macrophages, myeloid-derived suppressor cells, regulatory T cells, T helper cells, neutrophil, CD4+ T lymphocytes, CD8+cytotoxic T lymphocytes, and natural killer cells, et al. In addition to their well-known immunomodulatory function, recent studies revealed that immune cells could cooperate with tumor cells and bone cells to enhance bone metastasis and tumor progression. There are some patents targeting immune system to inhibit bone metastasis. Conclusion: Immune cells are instigated by tumor cells to enhance the occurrence and the development of bone metastasis. Taking full advantage of anti-tumor roles of immune cells may bring the promise of a possible cure for bone metastasis.

Background: Epithelial-Mesenchymal Transition (EMT) is the conversion of epithelial cells into mesenchymal phenotype generally observed during embryogenesis and wound healing as well as in malignant transformation. Several signaling pathways and transcription factors associated with EMT have been explored. Dietary phytochemicals that are multi-targeted agents which interfere with these pathways, assume preventive potential against pathologic EMT. Objective: The present review aims to provide a detailed description of the nature and characteristics of EMT in physiological and pathophysiological conditions and the scope of phytochemicals in its prevention. Method: Details regarding the initiation, progression as well as prevention of pathologic EMT and metastasis and recent patents on preventive phytochemicals were obtained from PubMed literatures and patent databases. Results: The phenotypic changes during EMT are regulated by transcription factors like Snail, Slug, Twist and Zeb, which are activated through diverse signaling pathways of TGF-β, NF-κB, Wnt and Notch. Scientific documentations till date have identified numerous phytocompounds that are potent enough to interfere with these signaling pathways, which in turn prevent pathological implications of EMT. Present review also discusses 28 recent patents on those phytocompounds. Conclusion: EMT is a significant pharmacological target for developing preventive agents to combat pathological conditions like malignancy. Many of the phytochemicals cited in this review are being enrolled for different phases of clinical trials for their efficacy. In spite of the major limitations regarding bioavailability, sensitivity and tolerance of these compounds, their synthetic analogs, formulations and efficient drug delivery systems are also being attempted which will hopefully generate productive and promising results in near future.

Gastrointestinal (GI) cancer, characterized by its leading mortality, is one of the most common cancers worldwide. The underlying mechanisms contributing to epithelial to mesenchymal transition (EMT) and metastasis of GI cancer are poorly understood. It is well known that a great number of transcription factors including FoxM1, KLF4, STAT3 and so forth, are associated with the process of EMT and have also been strongly implicated in the proliferation, migration, and invasion of GI cancer cells. Forkhead box M1 (FoxM1), a transcription factor of the Forkhead family, is strongly positive in GI cancers and can be regarded as an oncogene in GI cancers. A number of studies have reported that FoxM1 is involved in tumorigenesis and promotes cell proliferation, migration, invasion, angiogenesis, EMT and metastasis by targeting downstream genes. In this review, we will focus on highlighting the functions of FoxM1 in tumorigenesis, angiogenesis, invasion and metastasis of GI cancers, pointing out the roles of FoxM1 in GI cancer EMT through crosstalk with TGFβ, Wnt signaling pathways and ncRNA, to better understand the role of FoxM1 in GI cancer, and will discuss recent relevant patents concerning FoxM1 in tumor therapy.

Background: Different strategies against colon cancer are accompanied by treatment failure, because of drug toxicity toward normal cells and cancer stem cells (CSCs) resistance. However, previous patent evaluated liposome that encapsulated inhibitor of CSCs' aldehyde dehydrogenase (ALDH)1; disulfiram, for targeting breast CSCs. Liposome has disadvantages due to its hydrophobicity. Objectives: Designing hydrophilic nanoparticles has selectivity to release disulfiram in CC cells rather than in normal colonocytes based on variation in microenvironment between normal and cancer cells. Methods: Disulfiram was nanoformulated by its loading into cationic chitosan and coating with anionic albumin. Their selectivity and targeting were investigated using murine and human colon cancer cells compared to normal mice colon cells. Results: Zeta potential of the coated nanoparticles confirmed that albumin-layering confers negative charge (-10.3mv) for disulfiram-loaded chitosan nanoparticles (52.9mv). In slightly acidic medium of tumor, the ionic bond between albumin and chitosan hydrolyzed then the positive charge was reversed (47.6mv). Thus coated nanoparticles showed higher sustain release for disulfiram in tumor microenvironment than neutral pH and their uptake was higher in cancer cells than normal cells. This interpreted the highest selectivity of coated nanoparticles for enhancing apoptosis and eliminating CSCs in cancer cells. Conclusion: These patented coated nanoparticles were the most effective and selective for eradicating colon CSCs without insulting normal stem cells in comparison with disulfiram which was toxic to both normal and CSCs. This novel study that used charge switchable (hydrophilic) nanoparticles for targeting colon CSCs may represent a basis for future in vivo studies.

Background: The effect of bevacizumab (BVZ) for Cerebral Radiation Necrosis (CRN) was clear. However, the indications of BVZ had no reports. Objective: The aim of the paper was to investigate the indications of BVZ for CRN. Methods: Fourteen CRN patients (confirmed by imaging diagnosis) who underwent BVZ treatment between June 2011 and December 2014 were analyzed. BVZ was administered (5mg/kg body weight) once every three to four weeks for at least three cycles. Contrast-enhanced T1 MRI signal intensity changes were measured after BVZ treatment, to evaluate the clinical efficacy of BVZ and the recurrence and progression of CRN. Three patients who were followed for a longer duration were described in detail. The main observations included the indications and (the) use of BVZ for CRN. Results: Most patients undergoing BVZ treatment for CRN exhibited recurrence. One of the three patients described in detail was asymptomatic; CRN was reduced but then progressed, and a second course of BVZ failed. The other two patients showed obvious symptoms of primary CRN; CRN was significantly reduced, but then progressed with mild symptoms. A second short course of BVZ showed poor efficacy in one patient who demonstrated long-term stability after BVZ withdrawal. Second long course of BVZ resulted in further aggravation of CRN in the other patient, and a re-examination revealed spontaneous remission of CRN. Conclusion: Symptoms are an indication of BVZ treatment for primary CRN.