Recent Patents on Anti-Cancer Drug Discovery - Volume 12, Issue 1, 2017

Background: The proteasome is the major proteolytic site on the eukaryotic cell, degrading most of its short-lived or misfolded polypeptides. The ubiquitin-proteasome pathway has been found to play a fundamental role in the development of several pathologies, from cancer to neurodegenerative diseases, or even retroviral infections. Nature remains a powerful source for the discovery of bioactive compounds. Recently, a number of molecules of natural origin, as well as natural product derivatives, have been described as proteasome inhibitors. Most of these molecules directly block one or more catalytic sites of the 20S proteasome, but some of them act upstream of proteolytic degradation, for instance, inhibiting the ubiquitin tagging process. Objectives: The present review focuses on recent patents on proteasome inhibitors of natural origin, their derivatives and synthetic routes to obtain such molecules, as well as their application as a tool in chemotherapy. Conclusion: With several of these modulators of the ubiquitin-proteasome system under clinical trials, we hope that the next few years lead to the development of new pharmaceutical drugs and characterization of new proteasome inhibitors of natural origin or inspiration.

Background: Many laboratories have made intensive efforts to develop potent, selective, and orally bioavailable HDAC inhibitors (HDACIs). Novel HDACIs are being developed with the objective of improving potency and selectivity against specific types of cancers or non-cancer diseases. Objective: This updated patent review is an attempt to compile the work of various researchers of HDACIs from 2012 to mid 2016, and to enlighten and surprise both newcomers in this field and devoted medicinal chemists. Method: According to the literature research and the writers' own research experience in the discovery of HDAC inhibitors. Results: The inhibitors possessing new chemical scaffolds have attracted immense interest because they have the ability to improve HDAC isoform specificity and pharmaceutical properties. Focus is given to emerging medicinal chemistry principles and insights into the discovery and development of HDAC inhibitors. Conclusion: The development of effective HDACIs is shifting from trial-and-error approaches to sophisticated strategies. Effective profiling technologies will continue to have important utility.

Background: Protein homeostasis (proteostasis) is vital for the survival of cells in physiological and pathological conditions. Particularly, cancer cells are in constant state of cellular stress due to rapid proliferation and decreased quality control in proteosynthesis and therefore, are exceedingly dependent on the homeostasis pathways. Among the complex biological mechanisms regulating proteostasis are the highly conserved molecular chaperones, heat shock proteins (HSPs). HSPs assist cell survival by catalysing the proper folding of proteins, modulation of the apoptotic machinery and finally regulating the protein degradation machinery, providing either the stability or the degradation of selected proteins under stress conditions. Inevitably, HSPs are upregulated in malignancies and participate in different hallmarks of cancer, with indispensable roles in the onset and progression of the disease. Moreover, high levels of HSPs contribute to poor prognosis and treatment resistance in various cancers. Therefore these molecular chaperones present as attractive targets for anti-cancer therapy. Objective: This review describes how HSPs regulate different hallmarks of cancer and provides an overview on the most relevant patents which have recently appeared in the literature. Methods: The patents were extracted from Google Patents (2012-2016) while the clinical trial results were mined from www.clinicaltrial.gov. Results and Conclusion: Review of literature shows that the proteostatic functions of HSPs can modify different hallmarks of cancer. Moreover, targeting HSPs (notably HSP27, HSP70 and HSP90) exhibited positive results in clinical trials so far. However, more studies should be designed to optimize the efficacy of mono or combination therapy in various malignancies.

Background: Heat shock proteins (Hsp) are major chaperone molecules that have recently emerged as cancer therapeutic targets owing to their involvement in tumor cell proliferation, differentiation, invasion and metastasis. High levels of extracellular Hsp90 and Hsp70 have been closely associated with a wide range of human cancers. Accumulating evidence suggests that the pharmacological inhibition of these molecules can play a pivotal role in non-surgical cancer treatment. Efforts have been taken to develop monoclonal antibodies (mAbs) and antibody fragments targeting extracellular Hsp90 and Hsp70, alone or conjugated with standard anticancer agents, to control several types of cancer, such as breast, colon, prostate or melanoma. Objective: To provide an overview on the development of monoclonal antibodies and antibody fragments with capacity to bind Hsp90 and Hsp70, aiming at being used for cancer treatment. Methods: A systematic review was performed using European Patent Office and Google patents databases. Results: Based on the available literature and patents, we report the potential anticancer strategies based on these biological molecules. Conclusions: Supported by the recent developments in this field, Hsp targeting antibodies therapy may emerge for clinical use in the future for cancer patients, namely as antibody-drug conjugates combining the specificity of these antibodies with the potency of cytotoxic drugs.

Cancer accounts for a number of deaths each year. Consequently, prevention of this deadly disease is more challenging and hence the invention of new anticancer agents is of utmost importance. The current review elaborates the importance of indole designs as patented in the form of anticancer druglike molecules targeting different cites of biological arena. Specific attention was given to kinases such as platelet-derived growth factor receptor, vascular endothelial growth factor receptor and fibroblast growth factor receptor, Bruton's tyrosine kinase, anaplastic lymphoma kinase, Janus kinase, cyclin-dependent kinase aurora kinases A, B and C, checkpoint kinases, protein kinase R, Pim kinases, phosphoinositide 3- kinase, altered proteins kinases, polo-like kinase and many more. Moreover, the article summarizes the mode of action through the particular functions of kinases and the inhibitory potential of indole derivatives toward specific kinase. Certain patents gathered in the existing review article suggest that indole core can be a versatile foundation to discover drug-like kinase inhibitor molecules and modification of substituents existing on the indole moiety may have important impact on the pharmacokinetic and pharmacodynamics aspects of the resultant scaffolds. The information presented here would gather a great deal of interest to identify the new molecular designs bearing indole nucleus presenting novel anticancer drugs with a wide variety of biological targets involved in cancer pathology focusing on the inhibition of tyrosine kinases, serine/threonine-specific protein kinases, cyclin-dependent kinases, lipid kinases and altered protein kinases.

Background: High doses of Cisplatin (CP) can disrupt the normal functioning of various tissues such as ovaries and testis. In almost all the patients, spermiotoxicity of CP causes temporary or permanent azoospermia. Objective: In this study, the defensive effect of Melissa officinalis and vitamin E against testicular injuries caused by CP in male rats was evaluated. Method: Thirty six male rats were distributed into 6 groups. Group 1 was used as the negative control. In group 2, a single dose of CP (10 mg/kg) was administered on the first day. In groups 3 and 4, a single dose of CP (10 mg/kg) was administered on the first day and then treated with Melissa officinalis at 1000 mg/kg/day and vitamin E at 100 mg/kg/day for 7 consecutive days, respectively. Groups 5 and 6 were treated with Melissa officinalis and vitamin E for 7 consecutive days, respectively. After euthanasia, serum levels of testosterone, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) were evaluated. Testes were removed and weighed. Spermatic analysis was done on the tail of the epididymis. Tissue lipid peroxidation and activity of antioxidant enzymes in testes were evaluated as well. Results: The results showed that Melissa officinalis and vitamin E increased serum levels of testosterone, LH and FSH, weight of testes and sperm motility, count and vitality and decreased sperm cell abnormalities in rats given CP. Conclusion: Our results are useful in designing a medication of Melissa officinalis that can protect the testes against CP-induced testicular damage and infertility in cancerous male patients.

Background: Data mining publications and patent data can provide decision support for scientists, inventors and industry in the field of cancer research. Objective: The main objective of this article it to identify trends of research and patent generation productivity originating from Latin American countries in the field of cancer. Method: Publications were collected from the Scopus, Web of Science, PubMed database; and patents were collected from Latipat Espacenet databases. Data from January 1, 2000 until December 31, 2014 were searched for documents with specific words in cancer as a ‘‘topic’’ and a list of 20 Latin American countries as affiliation country. Results: A total of 12,989 items published and 244 patent applications including “cancer” were retrieved. Brazil, Mexico, Argentina, Chile and Peru were highest contributors in cancer research, while Brazil, Mexico, Cuba and Argentina were highest contributors in cancer patent applications. Conclusion: The analysis of the data from this study provides an overview of research and patent activity in Latin America in the cancer field, which can be useful to help health policy makers and people in academia to shape up cancer research in the future.