Recent Patents on Anti-Cancer Drug Discovery - Volume 13, Issue 4, 2018

Background: Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. Objectives: The study aimed to highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis. Methods: We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on “clinicaltrial.gov” to identify ongoing clinical trials and on “google. com/patents” and “uspto.gov” for recent patents exploring PARPIs in ovarian cancer. Results: Olaparib, Niraparib and Rucaparib are already approved for the treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum-sensitive and resistant disease). Conclusion: PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC.

Withanolides are C-28 ergostane steroids known to demonstrate some very interesting therapeutic properties. Numerous withanolides have been isolated from a variety of different plant species and can be employed to treat various types of cancers. Withanolides are indeed capable of demonstrating excellent anticancer, anti-inflammatory, and neuroprotective activities. Additionally, libraries of prepared withaferin A analogs incorporating an acyl, sulphate, amide and aldehyde functionality have demonstrated the most potential response. It is of particular interest to note that an acetyl group at either C-4, C-19 or C-27 enhances the anticancer effects. Since the majority of natural withanolides reported in patents are classified as “Type-A”, it is our opinion that there should now be a focus on developing “Type-B” withanolides and an investigation into their various therapeutic applications. Moreover, very little real innovation in synthetic methodologies has been reported which opens up huge possibilities for novel synthetic methodologies to be developed for the production of larger libraries new withanolides and their analogs to incorporate chemical diversity. In addition, since withanolides have the capability to conjugate with other anticancer compounds, this should encourage scientists to prepare lead compounds in cancer drug discovery.

Background: Massive vessel recruitment is required to sustain rapid tumor growth by delivering oxygen and nutrients. Current strategies to counteract angiogenesis are mostly aimed at reducing tumor vessel density. However, many of these drugs have been shown to trigger hypoxia, thus exacerbating tumor aggressiveness. Promising results come from a completely different approach based on the “normalization” of the endothelial layer and the consequent improvement of the vascular function. This new strategy would ameliorate drug delivery to the tumor meanwhile reducing invasiveness and metastatisation. Objective: Since endothelial metabolism has proved essential in the regulation of the angiogenic switch, many recent patents focus on agents able to inhibit specific metabolic pathways in Tumor- Associated Endothelial Cells (TECs) in order to provide vessel normalization. Here, we provide a review of the recent advances in the development of patents on agents targeting endothelial metabolism that have proved effective in several vascular disorders. Methods: Results of genetic and pharmacologic studies that brought to the development of patents for methods to counteract aberrant angiogenesis were analysed and sub-divided according to the specific metabolic pathway targeted. Results: Growing evidences indicate that targeting specific molecular players involved in the endothelial metabolic remodelling required to sustain aberrant angiogenesis, is a valuable therapeutic strategy that can be exploited in vascular disorders as well as in tumor angiogenesis. Conclusion: These findings might have important implications in clinics and could be particularly relevant to patients developing resistance to traditional anti-angiogenic drugs.

Background: The pharmaceutical development of endocrine disruptors could not achieve appropriate advances in the field of anticancer fight. Objective: Considerations on the principles of currently used endocrine therapies. Methods: Comparison of the results of genetic studies being performed on breast cancer cells treated with estrogens, synthetic estrogens and antiestrogens. Results: In breast cancer cells, increased estrogen concentrations amplify ER-signaling via a synergistic upregulation of both liganded and unliganded ER-activations and increased aromatase expression. The higher the upregulation of ER-signaling, the stronger is the tumor response. Low doses of synthetic estrogens exert an inhibition on the ligand-independent AF1-domain in breast cancer cells, while provoke compensatory activation on the superior, ligand-dependent AF2-domain of ERs and estrogen synthesis. Conversely, high doses of synthetic estrogens induce uncompensated genome-wide disruption in ER-regulated genes leading to toxic symptoms and unpredictable tumor responses. Treatment with antiestrogens, either ER-blockers or aromatase inhibitors, obstructs the crucial AF2-domain of ERs strongly deteriorating the activation of genomic machinery. Tumor responses to antiestrogen treatment depend on the compensatory activation of ER-signaling and the restoration of genomic stability. Recent patents provide methods for the conversion of ER-negative cancers to ER-positive ones improving the possibility of successful treatment. Conclusion: In tumor cells, the stabilization of genomic machinery and self-directed death may be achieved via a balanced activation of the AF1 and AF2 domains of ERs by natural estrogen treatment. In contrast, the blockade of either AF1 or AF2 domain by endocrine disruptors leads to toxic symptoms and unforeseeable tumor responses.

Background: Marine environment constitutes an almost infinite resource for novel anticancer drug discovery. The biodiversity of marine organisms provides a rich source for the discovery and development of novel anticancer peptides in the treatment of human cancer. Marine peptides represent a new opportunity to obtain lead compounds in biomedical field, particularly for cancer therapy. Objective: Providing an insight of the recent progress of patented marine peptides and presenting information about the structures and mechanistic mode of anticancer activities of these marine peptides. Methods: We reviewed recent progress on the patented anticancer peptides from marine organisms according to their targets on different signal pathways. This work focuses on relevant recent patents (2010-2018) that entail the anticancer activity with associated mechanism and related molecular diversity of marine peptides. The related cellular signaling pathways for novel peptides that induce apoptosis and affect tubulin-microtubule equilibrium, angiogenesis and kinase activity that are related to the anticancer and related pharmacological properties are also discussed. Results: The recent patents (2010-2018) of marine peptides with anticancer activity were reviewed, and the anticancer activity of marine peptides with associated mechanism and related molecular diversity of marine peptides were also discussed. Conclusion: Marine peptides possess chemical diversity and display potent anticancer activity via targeting different signal pathways. Some of the marine peptides are promising to be developed as novel anticancer agents.

Background: Solid tumors often contain hypoxic microenvironments due to abnormal vasculatures and outweighing demands of oxygen. Cancer cells rely on anaerobic respiration, leading to sequential acidic microenvironments. Hypoxic and acidic microenvironments cause genetic instability and activate signaling pathways, contributing to cancer progression and therapy resistance, and have become targets for developing novel anti-cancer agents. Objective: This article reviews recent advances in the development of novel anti-cancer drugs targeting hypoxic and acidic microenvironments. Methods: Recent patents and published literature related to anti-cancer agents targeting tumor hypoxic and acidic microenvironments were searched and reviewed. Key termed used in the searching included cancer, anti-cancer drug, neoplasm, clinical trials, tumor microenvironment, hypoxic microenvironment, acidic microenvironment, hypoxia-inducible factors, hypoxia; metabolism; Warburg effect and aerobic glycolysis. Results: A number of Hypoxia-Inducible Factor (HIF) inhibitors have been developed or discovered, but most of them have only exhibited indirect effects on HIFs, and a limited number of drugs are able to directly interfere with mRNA and protein of HIFs, the dimerization of α and β subunits, or the interaction between HIFs and its activators. The development of agents targeting acidic microenvironments focuses on V-ATPase, monocarboxylic acid transporters, Na+/H+ exchangers and carbonic anhydrases. Proton pump inhibitors as V-ATPase inhibitors have been applied in treating various tumors as an adjuvant therapy, but none of the other inhibitors has been approved for cancer treatment. Conclusion: Developing more specific agents, and seeking sensitive, applicable and accurate biomarkers may improve the efficacy of drugs targeting hypoxic and acidic microenvironments.

Background: Heliomycin (resistomycin), an antibiotic with broad spectra of biological activities including antimicrobial, antifungal, antiviral, and antiproliferative. However, an extremely low solubility in aqueous media and in the majority of organic solvents limits its practical application. Objective: Due to a high practical potential of heliomycin, new routes of structural modification are strongly required to improve its solubility. Conclusion: The patent claims a series of 4-aminomethyl derivatives of heliomycin as well as a pharmaceutical composition based on it. Application of Mannich aminomethylation allowed to diversify the structure of initial antibiotic and to obtain the derivatives with significantly improved water solubility and a potent antiproliferative efficacy.