Recent Patents on Anti-Cancer Drug Discovery - Volume 12, Issue 2, 2017

Abstract: Background: Microtubule dynamics plays a vital role in regulating crucial cellular functions and is one of the most attractive anticancer drug targets. Microtubule targeting agents (MTAs) such as the vinca alkaloids or taxanes, although are effective for cancer therapy, have adverse side effects. Another hindrance in their development is multiple drug resistance in tumor cells. These drawbacks have urged the need to develop novel MTAs from alternative sources, with better therapeutic efficacy. Recently, MTAs from marine sources have grabbed much attention due to unique tubulin binding features and remarkable ability to reduce tumor progression. Objective: The emphasis of the article is to provide an overview of some of the most promising marine derived MTAs and highlight their major characteristics in brief. Method: Patent databases such as USPTO, Espacenet and WIPO were searched systematically for recent patents published from 2006 up to 2016. Numerous data retrieved was analyzed critically, and only those patents focusing on the chemical synthesis and/or modifications of marine derived MTAs along with a significant demonstration of their in vitro and/or in vivo activity are summarized here. Results: Some of the marine derived MTAs have significant antiproliferative potency against a wide array of cancers and are also able to overcome multidrug resistance. Conclusion: The marine derived MTAs hold great potential in the field of cancer therapeutics and are gradually advancing in the clinical set up. A deeper understanding of the molecular mechanisms combined with innovative therapeutic regimen would lead to major advances in the field.

Background: Since the first reports of microRNAs and the advent of new sequencing technologies, a whole new world of regulatory non-conding RNAs (ncRNAs) has revolutionized our knowledge of the RNA dimension. Thousands of functional non-coding transcripts have been identified and grouped into new classes of ncRNAs attending to their origin and function. Despite the fact that we have just started to study ncRNAs, it is now clear that these new regulatory actors play an important role in most of the regulated biological processes and in almost all species. Objective: An overview of the state of the art in ncRNAs and the development, diagnosis and treatment of human cancer. Method: NcRNAs are deeply involved in the regulation of key genes that are associated with human cancer, representing a promising field for new therapies. This review summarizes the origin, structure and function of the most relevant new classes of ncRNAs, playing special attention to the studies that have related these new regulatory factors with the development of human cancer. Results: From a thorough literature review on scientific publications and patented applications, this review presents recent advances related to ncRNAs and human cancer. In addition, a selection of patents that use ncRNAs to develop new methodologies for the diagnosis and treatment of cancer is included and described in each class of ncRNAs. Conclusion: The regulatory potential of ncRNAs opens a new research field that will uncover new and promising aspects in the study of human cancer.

Background: Four decades of erroneous breast cancer therapy with antiestrogens yielded the chaotic mixture of manifestations of artificial ER-inhibition and compensatory activating ER-mutations together with unreckonable tumor responses. Objective: Due to the confusions between the anticancer and carcinogenic impacts of antiestrogens and synthetic estrogens, the old principle needs to be revised as concerns ER-signaling induced DNAdamage and breast cancer development. Method: Results of genetic studies on both estrogen- and antiestrogen-treated tumors were reanalyzed and associations among ER-blockade, compensatory restoration of ER-signaling and clinical behavior of cancers were investigated. Results: There are no direct correlations between estrogen concentrations and mammary tumor development; the highest risk for breast cancer is rather the severe defect of ER-signaling. Upregulation of ER-signaling induced by natural estrogens is a beneficial process even in tumor cells promoting their domestication and elimination while in case of antiestrogen administration; increased ER-signaling is a compensatory action to strengthen residual genome stabilization. In genetically proficient patients, extreme upregulation of ER-activity and estrogen synthesis provoked by antiestrogens provides transiently enhanced genomic stabilization with the promotion of spontaneous tumor death. Recent patents reveal correlations between activating ESR1 mutations and antiestrogen induced tumor response. Conversely, in the majority of patients with genetic defects, antiestrogen administration evokes weak counteractive increase in estrogen synthesis and ER-expression, which is not satisfactory in terms of tumor response. Conclusion: Activating mutations affecting ERs play key roles in both the machinery of genome stabilization of healthy cells and the restoration of altered genetic pathways of DNA-repair in tumor cells.

Background: Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix adhesion. These molecules play a role in processes such as cell growth and proliferation, differentiation, migration, cell trafficking, besides contributing to angiogenesis and tumor development. Given their biological role, integrins have been proposed as amenable targets in medicinal chemistry. In particular, αvβ3, αvβ5, αvβ6 and α5β1, integrins involved in tumor angiogenesis and metastasis, have been the subject of studies aimed at the discovery of novel cancer therapeutics. A large number of peptides and peptidomimetics based on the RGD (Arg-Gly-Asp) recognition sequence were developed in the past two decades as integrin ligands. Though such ligands have not been satisfactory as anti-angiogenic agents, their use as tools to achieve selective tumor targeting of anticancer drugs has been explored. Objective: In this review, we summarize recent literature and patent applications in which integrin peptidic and peptidomimetic ligands were conjugated to chemotherapeutic agents both with stable or cleavable bonds to achieve tumor targeted drug delivery. Methods: Relevant recent patents and literature in this field have been considered spanning the search from 2000 to 2016. Literature and patents were examined according to the different classes of cytotoxic drug targeted to integrins. Conclusion: In spite of the promising features of the conjugates, none of them has entered clinical trials. New efforts are focused on innovative approaches in the field such as the synthesis of new integrin ligands able to target a single integrin type or the employment of nanoparticles based drug delivery systems.

Background: Pain in oncology patients may be related to underlying disease process, as well as a side effect of chemotherapy and radiation. More than half of all patients with a diagnosis of cancer experience pain, which is often poorly controlled. As such, the treatment of pain in oncology patients demonstrates a significant need to develop new treatment options. Objective: This review summarizes 35 patents on the treatment of pain among cancer patients. Method: A thorough literature review of all patents filed in 2014 was conducted using PubMed and http://ep.espacenet.com/ as sources identify new treatment options for cancer pain. Results: Our literature search returned 35 patents filed in 2014 related to the treatment of pain in cancer patients. Conclusion: In 2014, a number of patents were filed for the treatment of pain among oncology patients. The great variety of chemical compounds presented indicates that there is a great variety in current research for cancer-related pain. The development of novel treatment options will hopefully lead to more effective therapies in the treatment of cancer-related pain.

Background: The multidrug resistance (MDR) of cancer cells has become a great barrier to the success of chemotherapy. Objective: In this study, quantitative structure activity relationship (QSAR) modeling was applied to 46 1,4-dihydropyridine structures (DHPs), and some selected compounds were docked. Methods: QSAR was used to generate models and predict the MDR inhibitory activity for a series of 1,4-dihydropyridines (DHP). The DHPs were built and optimized using the Sybyl program (x1.2 version). Descriptor generation was done by DRAGON package. Docking was carried out using Auto Dock 4.2 software. Multiple linear regression, and partial least square were performed as QSAR modelgeneration methods. External validation, cross-validation (leave one out) and y-randomization were used as validation methods. Results: The constructed model using stepwise-MLR and GA-PLS revealed good statistical parameters. In the final step all compounds were divided into two parts: symmetric (PLS) and asymmetric (MLR) 1,4-dihydropyridines and two other models were built. The square correlation coefficient (R2) and root mean square error (RMSE) for train set for GA-PLS were (R2 = 0.734, RMSE train = 0.26). Conclusion: The predictive ability of the models was found to be satisfactory and could be employed for designing new 1,4-dihydropyridines as potent MDR inhibitors in cancer treatment. 1,4- Dihydropyridine ring containing protonable nitrogen as scaffold could be proposed. Sulfur, ester, amide, acyle, ether, fragments are connected to a 1,4-dihydropyridine ring. Phenyl groups (with an electronegative substituent) as a lipophilic part are essential for the inhibitory effect.