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cancer drug discovery

Kishore Polireddy, Ruochen Dong, Peter R McDonald, Tao Wang, Brendan Luke, Ping Chen, Melinda Broward, Anuradha Roy, Qi Chen
BACKGROUND: Pancreatic cancer has an enrichment of stem-like cancer cells (CSCs) that contribute to chemoresistant tumors prone to metastasis and recurrence. Drug screening assays based on cytotoxicity cannot identify specific CSC inhibitors, because CSCs comprise only a small portion of cancer cell population, and it is difficult to propagate stable CSC populations in vitro for high-throughput screening (HTS) assays. Based on the important role of cancer cell epithelial-to-mesenchymal transition (EMT) in promoting CSCs, we hypothesized that inhibition of EMT can be a useful strategy for inhibiting CSCs, and therefore a feasible approach for HTS can be built for identification of CSC inhibitors, based on assays detecting EMT inhibition...
2016: PloS One
András Füredi, Szilárd Tóth, Kornélia Szebényi, Veronika F S Pape, Dóra Türk, Nóra Kucsma, László Cervenák, József Tóvári, Gergely Szakács
Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study our aim was to catalogue various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp) overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp...
October 19, 2016: Molecular Cancer Therapeutics
Maria Rosaria Carratù, Anna Signorile, Domenico De Rasmo, Antonia Reale, Angelo Vacca
BACKGROUND: The serine-threonine protein phosphatase 2A (PP2A) regulates multiple cell signaling cascades and its inactivation by viral oncoproteins, mutation of specific structural subunits or upregulation of the cellular endogenous inhibitors may contribute to malignant transformation by regulating specific phosphorylation events. Pharmacological modulation of PP2A activity is becoming an attractive strategy for cancer treatment. Some compounds targeting PP2A are able to induce PP2A reactivation and subsequent cell death in several types of cancer...
October 14, 2016: Current Medicinal Chemistry
Jae-Woo Jang, Yeonhwa Song, Kang Mo Kim, Jin-Sun Kim, Eun Kyung Choi, Joon Kim, Haengran Seo
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide and is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic agents, novel therapeutic strategies are needed to improve survival in HCC patients. METHODS: Here, we developed a fluorescence image-based phenotypic screening system in vitro to identify HCC-specific drugs in co-cultures of HCC cells with hepatocytes. To this end, we identified two distinctive markers of HCC, CHALV1 and AFP, which are highly expressed in HCC cell lines and liver cancer patient-derived materials...
October 18, 2016: BMC Cancer
Rama Raghavan, Stephen Hyter, Harsh B Pathak, Andrew K Godwin, Gottfried Konecny, Chen Wang, Ellen L Goode, Brooke L Fridley
BACKGROUND: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among women in the United States (5 % of cancer deaths). The standard treatment for patients with advanced EOC is initial debulking surgery followed by carboplatin-paclitaxel combination chemotherapy. Unfortunately, with chemotherapy most patients relapse and die resulting in a five-year overall survival around 45 %. Thus, finding novel therapeutics for treating EOC is essential. Connectivity Mapping (CMAP) has been used widely in cancer drug discovery and generally has relied on cancer cell line gene expression and drug phenotype data...
October 19, 2016: BMC Genomics
Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
Angel R de Lera, A Ganesan
The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders...
2016: Clinical Epigenetics
Jessica E Maxwell, Scott K Sherman, James R Howe
Pancreatic neuroendocrine tumors (PNET) are rare tumors, but have been increasing in incidence. Although typically thought of as indolent, more than half of patients present with metastatic disease. For many years, the only mutations commonly known in these tumors were those in the MEN1 gene. Recently, the genetics underlying PNETs have been further defined through exome sequencing. The most frequent alterations found in sporadic PNETs are in MEN1, DAXX/ATRX, and a variety of genes in the mTOR pathway. Confirmation of these mutations has prompted trials with a number of drugs active in these pathways, and two drugs were eventually approved in 2011-sunitinib and everolimus...
October 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Chun-Hui Zhang, Kai Chen, Yan Jiao, Lin-Li Li, Ya-Ping Li, Rong-Jie Zhang, Ming-Wu Zheng, Lei Zhong, Shen-Zhen Huang, Chun-Li Song, Wan-Ting Lin, Jiao Yang, Rong Xiang, Bing Peng, Jun-Hong Han, Guang-Wen Lu, Yu-Quan Wei, Sheng-Yong Yang
Herein we report the sophisticated process of structural optimization towards a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo, but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays, and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an)...
October 14, 2016: Journal of Medicinal Chemistry
Romina J Pagliero, Diego S D'Astolfo, Daphne Lelieveld, Riyona D Pratiwi, Sonja Aits, Marja Jaattela, Nathaniel I Martin, Judith Klumperman, David A Egan
The lysosomal cell death (LCD) pathway is a caspase 3-independent cell death pathway that has been suggested as a possible target for cancer therapy, making the development of sensitive and specific high-throughput (HT) assays to identify LCD inducers highly desirable. In this study, we report a two-step HT screening platform to reliably identify such molecules. First, using a robust HT primary screen based on propidium iodide uptake, we identified compounds that kill through nonapoptotic pathways. A phenotypic image-based assay using a galectin-3 (Gal-3) reporter was then used to further classify hits based on lysosomal permeabilization, a hallmark of LCD...
October 2016: Assay and Drug Development Technologies
Emma Danelius, Mariell Pettersson, Matilda Bred, Jaeki Min, M Brett Waddell, R Kiplin Guy, Morten Grøtli, Mate Erdelyi
Protein-protein interactions that have large, flat and featureless binding sites are difficult drug targets. In the development of their modulators conventional drug discovery strategies are often unsuccessful. Gaining a detailed understanding of the binding mode of protein-protein interaction inhibitors is therefore of vast importance for their future pharmaceutical use. The MDM2/p53 protein pair is a highly promising target for cancer treatment. Disruption of the protein complex using p53 α-helix mimetics has been shown to be a successful strategy to control p53 activity...
October 12, 2016: Organic & Biomolecular Chemistry
Bincy Baby, Priya Antony, Walaa Al Halabi, Zahrah Al Homedi, Ranjit Vijayan
Polypharmacology, the discovery or design of drug molecules that can simultaneously interact with multiple targets, is gaining interest in contemporary drug discovery. Serine/threonine kinases are attractive targets for therapeutic intervention in oncology due to their role in cellular phosphorylation and altered expression in cancer. Quercetin, a naturally occurring flavonoid, inhibits multiple cancer cell lines and is used as an anticancer drug in Phase I clinical trial. Quercetin glycosides have also received some attention due to their high bioavailability and activity against various diseases including cancer...
2016: Drug Design, Development and Therapy
Zahra Razaghi-Moghadam, Razieh Abdollahi, Sama Goliaei, Morteza Ebrahimi
In the past few years, many researches have been conducted on identifying and prioritizing disease-related genes with the goal of achieving significant improvements in treatment and drug discovery. Both experimental and computational approaches have been exploited in recent studies to explore disease-susceptible genes. The experimental methods for identification of these genes are usually time-consuming and expensive. As a result, a substantial number of these studies have shown interest in utilizing computational techniques, commonly known as gene prioritization methods...
October 7, 2016: Journal of Biomedical Informatics
Julian Gingold, Ruoji Zhou, Ihor R Lemischka, Dung-Fang Lee
The elucidation of cancer pathogenesis has been hindered by limited access to patient samples, tumor heterogeneity and the lack of reliable model organisms. Characterized by their ability to self-renew indefinitely and differentiate into all cell lineages of an organism, pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide a powerful and unlimited source to generate differentiated cells that can be used to study disease biology, facilitate drug discovery and development, and provide key insights for developing personalized therapies...
September 2016: Trends in Cancer
Bhumika Wadhwa, Rashmi Dumbre
Prostate (CaP) cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance. The recent discovery that AR signaling persists during systemic castration via intratumoral production of androgens led to the development of novel anti-androgen therapies...
October 6, 2016: Chemico-biological Interactions
Gennady M Verkhivker
Protein kinases are versatile molecule switches that govern functional processes in signal transduction networks and regulate fundamental biological processes of cell cycle and organism development. The continuous growth of biological information and a remarkable breath of structural, genetic, and pharmacological studies on protein kinase genes have significantly advanced our knowledge of the kinase activation, drug binding and allosteric mechanisms underlying kinase regulation and interactions in signaling cascades...
October 6, 2016: Current Medicinal Chemistry
Hansaim Lim, Aleksandar Poleksic, Yuan Yao, Hanghang Tong, Di He, Luke Zhuang, Patrick Meng, Lei Xie
Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying the genome-wide off-targets of lead compounds or existing drugs will be critical for designing effective and safe drugs, and providing new opportunities for drug repurposing. Although many computational methods have been developed to predict drug-target interactions, they are either less accurate than the one that we are proposing here or computationally too intensive, thereby limiting their capability for large-scale off-target identification...
October 2016: PLoS Computational Biology
Caleb Mawuli Agbale, Marlon Henrique Cardoso, Isaac Kojo Galyuon, Octávio Luiz Franco
The accidental discovery of cisplatin some 50 years ago generated renewed interest in metallopharmaceuticals. Beyond cisplatin, many useful metallodrugs have been synthesized for the diagnosis and treatment of various diseases, but toxicity concerns, and the propensity to induce chemoresistance and secondary cancers make it imperative to search for novel metallodrugs that address these limitations. The Amino Terminal Cu(ii) and Ni(ii) (ATCUN) binding motif has emerged as a suitable template to design catalytic metallodrugs with nuclease and protease activities...
September 30, 2016: Metallomics: Integrated Biometal Science
Fangkun Liu, Jing Huang, Bo Ning, Zhixiong Liu, Shen Chen, Wei Zhao
Patient-derived cell lines and animal models have proven invaluable for the understanding of human intestinal diseases and for drug development although both inherently comprise disadvantages and caveats. Many genetically determined intestinal diseases occur in specific tissue microenvironments that are not adequately modeled by monolayer cell culture. Likewise, animal models incompletely recapitulate the complex pathologies of intestinal diseases of humans and fall short in predicting the effects of candidate drugs...
2016: Frontiers in Pharmacology
Qurrat-Ul- Ain, Haroon Khan, Mohammad S Mubarak, Aini Pervaiz
An alkaloid is a class of naturally occurring organic nitrogen-containing compounds that are frequently found in the plant kingdom. Many alkaloids are valuable medicinal agents that can be utilized to treat various diseases including malaria, diabetics, cancer, cardiac dysfunction etc. Similarly, platelet aggregation beyond the purpose of homeostasis is the underlying cause of blood clotting related diseases. This review presents a thorough understanding of alkaloids as antiplatelet agents with a possible mechanism of action based on the literature of the last decade...
2016: Frontiers in Pharmacology
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