Recent Patents on Anti-Cancer Drug Discovery - Volume 13, Issue 2, 2018

Background: IL-17A is a founding member of the IL-17 family that has been implicated in the pathogenesis of inflammatory-associated diseases such as cancer and autoimmune disease. In cancer, IL-17A participates in many key events for tumor development, in part by affecting innate and adaptive immune system and also by direct modulation of many pro-tumor events. Moreover, IL-17A dysregulation at the site of inflammation is associated with rheumatoid arthritis, multiple sclerosis, psoriasis, among others. IL-17A has emerged as a topic of interest and is under profound investigation for its involvement in several types of inflammatory-associated diseases. Objective: This review aims to present an overview of the state of the art of IL-17A role in cancer and inflammation, as well as to describe recent patents targeting IL-17A with relevant clinical and biological properties for the prevention and treatment of cancer and inflammatory diseases. Methods: Relevant information was obtained by searching in PubMed using IL-17A or IL-17, cancer and inflammation as keywords, while relevant patents were obtained mainly from Google Patents. Results: Literature data indicated IL-17A as important biomolecule in the physiopathology of cancer and inflammatory diseases. Whereas, novel patents (2010 to 2017) targeting IL-17A are focused mainly on describing strategies to modulate IL-17A per se, co-modulation by bispecific antibodies to blocking IL-17A and important cytokines for IL-17A functions, upstream mechanisms and compounds to regulate IL-17A expression. Conclusion: The promising effects of patented agents against IL-17A may open new opportunities to therapeutic intervention targeting at different levels of involvement in the pathogenesis of cancer and inflammatory diseases.

Background: Ovarian cancer remains the most common lethal gynecologic malignancy. The therapeutic gains with the use of traditional cytotoxic chemotherapy in advanced stage disease remain limited, reflecting the need for novel therapies. Poly(ADP-ribose) polymerase (PARP) inhibitors have recently demonstrated a significant therapeutic effect in patients with recurrent, high grade serous ovarian cancer, both in the treatment of existing disease and in prolonging the disease-free interval. Objective: The purpose of this article is to discuss PARP inhibitor use in patients with advanced stage ovarian cancer, and to extensively review the existing clinical literature and related patents. Methods: A comprehensive PUBMED literature review was conducted to identify all published phase 2 and phase 3 clinical trials involving PARP inhibitors in advanced epithelial ovarian cancer. Further, several patents related to PARP inhibitor use, companion diagnostic tests, and the development of biomarkers to predict PARP inhibitor responsiveness are described. Results: PARP inhibitors have demonstrated significant clinical activity in both BRCA deficient and wild-type patient cohorts, with all three FDA-approved PARP inhibitors demonstrating efficacy irrespective of BRCA mutation status in patients with advanced epithelial ovarian cancer. Conclusion: PARP inhibitors have emerged as an exciting new drug class in the treatment of epithelial ovarian cancer. Ongoing studies are aimed at improving our ability to identify ideal candidates for PARP inhibitor therapy, as well as to identify and target mechanisms of drug resistance, and novel combinatorial approaches.

Background: The anthracene-9,10-dione (anthraquinone) derivatives represent an exceptionally valuable class in anticancer drug development. An outstanding antitumor potency of the anthracycline antibiotics attracted the attention of medicinal chemists since the discovery of these chemotypes. The prominent anthraquinone-based drugs doxorubicin, mitoxantrone as well as more recent epirubicin, idarubicin, and valrubicin are successfully used in chemotherapy of hematological malignancies and solid tumors. The anthraquinone core remains a promising scaffold for the search of new optimized drug candidates. Objective: In this study, we analyze the progress in discovery and development of antitumor anthracene- 9,10-diones based on patent and journal publications in 2008-2017. The main goal is to dissect novel chemotypes of anthraquinone derivatives; other important issues such as the success in bioconjugate chemistry of anthraquinone containing agents as well as the patents on new applications of anthracyclines are beyond the scope of this review. Conclusion: A number of newly discovered natural products, the perspective directions for chemical modifications to optimize the anticancer properties, and novel intracellular targets demonstrate that anthracene- 9,10-diones deserve further in-depth investigation as an important source of drug candidates.

Background: Modifications of lipid metabolism have been progressively accepted as a hallmark of tumor cells and in particular, an elevated lipogenesis has been described in various types of cancers. Objective: Important or deregulated activity of the mevalonate pathway has been demonstrated in different tumors and a wide range of studies have suggested that tumor cells are more dependent on the unceasing availability of mevalonate pathway metabolites than their non-malignant complements. Methods: This study provides an overview of the state of the art of statins treatment on human cancer. Results: In recent times, various actions have been proposed for statins in different physiological and pathological conditions beyond anti-inflammation and neuroprotection activity. Statins have been shown to act through mevalonate-dependent and -independent mechanisms able to affect several tissue functions and modulating specific signal transduction pathways that could account for statin pleiotropic effect. Based on their characteristics, statins represent ideal candidates for repositioning in cancer therapy. Conclusion: In this review article, we provide an overview of the current preclinical and clinical status of statins as antitumor agents. In addition, we evaluated various patents that describe the role of mevalonate pathway inhibitors and methods to determine if cancer cells are sensitive to statins treatment.

Background and Objective: Lenvatinib is an oral, multitargeted Tyrosine Kinase Inhibitor (TKI) of Vascular Endothelial Growth Factor Receptors (VEGFR1-VEGFR3), fibroblast growth factor receptors (FGFR1-FGFR4), Platelet-Derived Growth Factor Receptor (PDGFR)α, rearranged during transfection (RET), and v-kit (KIT) signaling networks implicated in tumor angiogenesis. Method: Here, we review the scientific literature about lenvatinib in the treatment of thyroid cancer. Results: In vitro studies have shown antineoplastic activity of lenvatinib in Differentiated Thyroid Cancer (DTC), mainly because of its antiangiogenetic effects, but a slight effect on thyroid cancer cell proliferation has been shown. In vivo Phase II, and Phase III studies in patients with aggressive DTC not responsive to radioiodine, have shown that lenvatinib administration was associated with an amelioration in Progression-Free Survival (PFS) with respect to placebo (median PFS 18.2 vs. 3.6 months). However, overall survival was not significantly changed. Lenvatinib is also effective in patients resistant to sorafenib as salvage therapy. Adverse effects of any grade occur in more than 40% of lenvatinib-treated patients, mainly hypertension, diarrhea, asthenia or fatigue, nausea, decreased appetite, and decreased weight. Discontinuations of the therapy because of adverse effects occur in about 14% of patients. Moreover, deaths considered to be drug-related can occur. Conclusion: On the basis of the above-mentioned considerations, it is necessary to prove the effectiveness of lenvatinib in the context of associated moderate to severe toxicities requiring frequent dose reduction and delays, and for this reason, many interesting patents have been recently applied.

Background: Glioblastoma (GBM) is the most aggressive and common brain tumor in adults, currently lacking effective life-prolonging and recurrence-preventing therapy; median survival of GBM patients stands at only 14-16 months. Increasing lines of evidence indicate that Anaplastic lymphoma kinase (ALK), a druggable tyrosine kinase receptor over-expressed in GBM, represents a potential therapeutic target in this tumor. Objective: An overview of the state of the art and the existing recent patents regarding potential exploitation of ALK as a therapeutic target and/or diagnostic/prognostic factor in GBM. Method: Recent literature and patents focusing on or including ALK pre-clinical and clinical research in GBM have been identified and reviewed, and are discussed according to their potential use. Results: Numerous recent ALK-related patents were identified. They were reviewed/analyzed in relation to previously published research and categorized based on their potential in GBM: i) diagnosis/ prognosis, ii) drug-based therapeutic targeting of ALK using a single compound or combination schemes and iii) therapeutic ALK targeting by other means, e.g. ALK vaccination. Conclusion: ALK targeting holds promise as a novel therapeutic approach in GBM, especially in combination schemes allowing multi-target therapy. Such schemes may incorporate detection-guided therapy and utilize next generation inhibitory compounds with improved central nervous system penetration. Moreover, identification of ALK-mediated molecular pathway(s) related to GBM carcinogenesis/ pathology and putative therapy resistance is of high priority and warrants further exploitation.

Background: Tumor cells may be expressed as a result of oxidative stress. The extent of oxidative stress correlates with the aggressive and metastatic potency of cancer. Objective: One simple way to control prostate cancer is through chemoprevention which refers to the administration of natural or synthetic agents to block, reverse, or delay the process of carcinogenesis. The most chemopreventive agents are antioxidants in nature. Methods: In this review, we summarized the effects of dietary antioxidants with a focus on their molecular mechanisms and possible roles in the treatment of prostate cancer cells. We also reported the recent outcomes of laboratory and/or clinical trials of antioxidants in prostate cancer patients. Results: Numerous pre-clinical studies showed that antioxidants protect DNA against being damaged by Reactive Oxygen Species (ROS), thereby genetic mutations causing cancer are likely to be prevented. However, the clinical trial results showed that antioxidants have yielded mixed outcomes or benefitted only a subgroup of the population. Conclusion: A greater understanding of the molecular events associated with antioxidants will enhance the development of treatment and could result in better strategies for the chemoprevention of prostate cancer. Recent patents also suggest that anti-oxidant compounds can be effective for the prevention and the treatment of prostate cancer.

Background: α-Solanine, the most important and active component of Solanum nigrum, was found to have anti-cancer activity on multiple cancer cells. However, its effects on colorectal cancer (CRC) and associated molecular mechanisms remain to be further elucidated. Objective: In this study, we investigated the anti-cancer effects of α-solanine against CRC cells in vitro and in vivo. Materials & Methods: Cell viability was measured using Cell Counting Kit-8 (CCK-8) assay; cell cycle was analyzed with a Cycletest Plus DNA Reagent Kit; cell apoptosis was detected by flow cytometer; cell migration and invasive ability was determined by Transwell assays; S100P protein expression was also analyzed by western blotting; lentiviral vectors expressing shRNA targeting the S100P gene. Results: We demonstrated that α-solanine inhibited CRC cell (SW480, SW620 and HT-29) growth as well as migration and invasion, induced cell cycle arrest and apoptosis in vitro, and suppressed tumor growth in vivo. Moreover, we observed that S100P expression was downregulated by α-solanine. Overexpression of S100P partially reversed the α-solanine-induced growth inhibition of CRC cells. Conversely, knockdown of S100P by lentiviral-mediated RNAi resulted in significantly promoting the α-solanine-induced growth inhibition. Conclusion: These findings suggest that α-solanine is a potential agent for the treatment of CRC, and the anti-tumor effect of α-solanine in the CRC cells may be mediated at least partly by the downregulation of S100P.

Background: Vincristine (VCR) resistance can lead to cancer chemotherapy failure. Although changes in gene expression are responsible for drug resistance, the specific identities and roles of these genes remain unclear. Objective: In this study, we aimed to identify differentially expressed genes and mechanisms of VCR resistance in colorectal cancer (CRC) cells. Methods: A VCR-resistant CRC cell line (HCT-8/VCR) was established, and differentially expressed proteins between HCT-8 and HCT-8/VCR cells were screened using a human cytokine array; the results were confirmed by reverse transcription polymerase chain reaction and Western blotting. Furthermore, differentially expressed proteins were downregulated using siRNA, and cell proliferation and apoptosis were assessed by Cell Counting Kit-8 assay and flow cytometry, respectively. Results: Compared with HCT-8 CRC cells, HCT-8/VCR cells showed downregulation of lipocalin 2 (LCN2). We found that siRNA-mediated downregulation of LCN2 in HCT-8 cells significantly increased VCR resistance. Furthermore, when we downregulated LCN2, we observed significant decreases in apoptosis, but no significant effect on cell cycle. Conclusion: Overall, these results demonstrate that LCN2 plays an important role in VCR resistance and is a potential therapeutic target for this disease.

Background: P-glycoprotein (P-gp) causes the efflux of cancer chemotherapy drugs from tumor cells, so its inhibition can be one target for designing and synthesis of new anticancer drugs. Objective: In this study, new compounds of 1,4-dihydropyridine (DHP) were recommended as inhibitors of P-gp. Methods: We synthesized new symmetrical DHP with 36% - 43% yield by the reaction of new reactants. In biological studies, these compounds have high lipophilicity, and thus low water solubility. Four reactants I with different reactivity was computed and compared using DFT study. The LUMO-map was differently distributed on each reactant. Amine intermediate underwent tautomerism as a transition state and it seems to play important role in reaction progress. Calculations were performed to select suitable reactants. Results: Two different reactants I, including one polar group and a non-polar group, were used to produce asymmetric compounds with 49% - 60% yield. These asymmetric DHPs were more soluble than symmetric DHPs. In the final step, another selected symmetric product (by the elimination of chlorine atom) was synthesized in high yield (74%) by using DFT study. Conclusion: In this study, selected reactants by DFT calculation have increased the yield of reaction from 36% to 74% without any catalyst. The diversity of products is a noticeable topic. Racemic asymmetric compounds with R and S enantiomers have the potential for enantiomeric separation. Each of these enantiomers could have a different physiological effect.