Recent Patents on Anti-Cancer Drug Discovery - Volume 8, Issue 2, 2013

Inosine monophosphate dehydrogenase (IMPDH), an NAD-dependent enzyme that controls de novo synthesis of guanine nucleotides, has received considerable interest in recent years as an important target enzyme, not only for the discovery of anticancer drugs, but also for antiviral, antiparasitic, and immunosuppressive chemotherapy. The field of IMPDH inhibitor research is highly important for providing potential therapeutics against a validated target for disease intervention. This patent review examines the chemical structures and biological activities of recently reported IMPDH inhibitors. Patent databases SciFinder and Espacenet and Delphion were used to locate patent applications that were published between January 2002 and July 2012, claiming chemical structures for use as IMPDH inhibitors. From 2002 to 2012, around 47 primary patent applications have claimed IMPDH inhibitors, which we analyzed by target and applicant. The level of newly published patent applications covering IMPDH inhibitors remains high and a diverse range of scaffolds has been claimed.

The response of the body to cancer is not a unique mechanism and has many parallels with inflammation and wound healing. Unresolved inflammation generates a microenvironment favorable for cellular transformation and the growth of cancer cells. Chronic tissue damage triggers a repair response that includes the production of growth factors, cytokines and chemokines. Cytokines and chemokines have a crucial role in cancer-related inflammation with consequent, direct and indirect effects on the proliferative and invasive properties of tumor cells. In view of the multifactorial functions of cytokines and chemokines in tumorigenesis, the elucidation of their roles will further advance our understanding of the patho-physiological processes of tumor development and highlights potential innovative anti-cancer strategies. Despite recent advances, main anti-cancer therapies, namely surgery, radiation therapy and chemotherapy, are limited in their ability to treat minimal and metastatic residual disease. Furthermore, the benefit of conventional therapies is often limited by collateral damage to normal tissues. Immunotherapy is a new avenue of cancer treatment being investigated by researchers and clinicians for different cancer types. The aim of this paper is to analyze the recent patents and scientific reviews on the major cytokine/chemokine pathways involved in cancer immunotherapy and discuss their basic biology, clinical relevance and potential directions for future anti-cancer therapeutic applications.

Breast cancer is the commonest type of malignant tumor in women, comprising of about 30% of all cancers in women worldwide. In the past decades, the mortality of breast cancer patients has significantly been reduced due to the adoption of periodic breast cancer screening and the emergence of various treatments, such as radiotherapy, chemotherapy, and surgery. Currently, chemotherapy is one of the most effective treatments for breast cancer. Its side effects, however, pose a long-term challenge on a patient's health. Thus, it is highly desirable to develop new therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made to develop targeted drug delivery systems for breast cancer treatment. In this review, we intend to systematically examine recent progresses made along these directions. We highlighted various delivery carriers designed for directing the diffusion of therapeutic agents inside tumors to kill or suppress breast cancer cells. These carriers include molecular-recognitionelement modified anticancer agents, stem cells that have tropism to breast cancers, nanoparticle-based anticancer drugs, and anticancer peptides. In particular, we discussed recent patents on the new targeted therapeutic delivery systems, with an emphasis on triple-negative breast cancer therapies.

Literary data suggest apparently ambiguous interaction between menopausal status and obesity-associated breast cancer risk based on the principle of the carcinogenic capacity of estrogen. Before menopause, breast cancer incidence is relatively low and adiposity is erroneously regarded as a protective factor against this tumor conferred by the obesity associated defective estrogen-synthesis. By contrast, in postmenopausal cases, obesity presents a strong risk factor for breast cancer being mistakenly attributed to the presumed excessive estrogen-production of their adipose-tissue mass. Obesity is associated with dysmetabolism and endangers the healthy equilibrium of sexual hormone-production and regular menstrual cycles in women, which are the prerequisites not only for reproductive capacity but also for somatic health. At the same time, literary data support that anovulatory infertility is a very strong risk for breast cancer in young women either with or without obesity. In the majority of premenopausal women, obesity associated insulin resistance is moderate and may be counteracted by their preserved circulatory estrogen level. Consequently, it is not obesity but rather the still sufficient estrogen-level, which may be protective against breast cancer in young adult females. In obese older women, never using hormone replacement therapy (HRT) the breast cancer risk is high, which is associated with their continuous estrogen loss and increasing insulin-resistance. By contrast, obese postmenopausal women using HRT, have a decreased risk for breast cancer as the protective effect of estrogen-substitution may counteract to their obesity associated systemic alterations. The revealed inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology and promotes primary prevention measures. New patents recommend various methods for the prevention and treatment of obesity-related systemic disorders and the associated breast cancer.

In this review, we discuss the current patents concerning aryl/heteroaryl thiosemicarbazone derivatives as regards to their activities and properties, including coordination (chelation) properties. The mode of action of the aryl/heteroaryl thiosemicarbazone derivatives involves metal coordination with proteins or biological fluids that have metal ions in their structure. Additionally, these molecules can also form multiple hydrogen bonds through their (thio) amide and N3 nitrogen that ensure a strong interaction with the receptor. In some cases, strong π-π interactions can be observed too. Special attention is given to pyridyl, bis-pyridyl, benzoylpyridyl and isatin thiosemicarbazone derivatives that exhibit significant anticancer, antiviral and other activities in free and in metal complexed forms. This key biological role is often related with their capability to inhibit the enzyme ribonucleotide reductase, similar to what is observed with potent anticancer drugs such as Triapine and methisazone. Recent studies have revealed that thiosemicarbazone can also inhibit topoisomerase II α enzyme. Thiosemicarbazone derivatives form coordination complex with various metals such as Zn, Cu, Fe, Co, Ni, Pt, Pd, etc., and these complexes provide better activities than the free thiosemicarbazones. Recent patents show that the controlled or sustained release dosage form of the thiosemicarbazone derivatives along with ionizing radiations is used for the treatment of proliferative diseases (US20110152281, US20110245304, US20120172217).

Introduction: The aim of our study was to correlate Maspin expression, a serine protease with possible antiangiogenic and antiproliferative effects, with angiogenesis and to realize a synthesis of the literature data regarding the novel patented compounds used in colorectal cancer (CRC). Materials and methods: In 110 cases with CRC, immunohistochemical stains were performed using Maspin, p53, VEGFA, CD31, and CD105. The results were correlated with the tumor stage and microsatellite status. A new scoring system for Maspin, based on the dual cytoplasmic-nuclear expression, with possible predictive value, was proposed. Results: The angiogenesis presented an oscillating pattern, the VEGF expression was more intense in Stage IV, but the endothelial area that quantified with both CD31 and CD105 was smaller than in those cases diagnosed in Stages II and III. Most of the p53 negative cases with Maspin nuclear predominance, which seems to respond to 5-Fluorouracil, were microsatellite instability (MSI) cases. In Stage II, Maspin nuclear positivity was more specific for pT4 tumors and aggressive cases with high p53 index. Thirty-three percent of CRC diagnosed in Stage II and 27% of those from Stage III presented Maspin expression in the endothelial cells. No cases from Stage IV had Maspin vascular positivity. Conclusions: Maspin nuclear expression, associated with p53 ones, might be used either to select the high-risk microsatellite stable (MSS) colorectal carcinomas diagnosed in Stage II or those MSI cases which can respond to 5-Fluorouracil.

Isoliquiritigenin (ISL), a licorice chalconoid, is a bioactive agent with chemopreventive potential that has been patented for tumor treatment in China. This study investigated the mechanisms of ISL-induced apoptosis in ovarian carcinoma SKOV-3 cells. Cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. The apoptotic rate was determined via flow cytometry using an annexin V-FITC apoptosis detection kit. The intracellular reactive oxygen species (ROS) levels were assessed using a 2,7-dichlorofluorescein probe assay. Malondialdehyde (MDA) formation was determined via thiobarbituric acid reactive substance test. The expressions of growth arrest and DNA damage-inducible gene (GADD153/CHOP), 78 kDa glucose-regulated protein (GRP 78), α-subunit of eukaryotic initiation factor 2 (eIF2α) phosphorylation, activating transcription factor 6α (ATF6α), and unspliced form of X-box binding protein1 (XBP1U) were analyzed via Western blot. Caspase-3 and caspase-12 activities were assessed using a fluorometric kit. Findings indicate that ISL significantly inhibits SKOV-3 cell proliferation, increases intracellular ROS levels, and causes SKOV-3 cell apoptosis. Moreover, ISL-exposed SKOV-3 cells trigger endoplasmic reticulum (ER) stress, as indicated by the enhancement of ER stress-related molecules p-eIF2α, GADD153/CHOP, GRP78, XBP1 expression, and cleavage of ATF6α. However, caspase-12 inhibitor (Z-ATAD) effectively and partially prevents ROS and MDA formation and inhibits ISL-induced SKOV-3 cell apoptosis. ISL induces apoptosis via ER stress-triggered signaling pathways in SKOV-3 cells. ER stress-induced cancer cell apoptosis has been discussed in some patents.