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https://www.readbyqxmd.com/read/28526744/combining-properties-of-different-classes-of-pi3k%C3%AE-inhibitors-to-understand-molecular-features-that-confer-selectivity
#1
Grace Q Gong, Jackie D Kendall, James Mj Dickson, Gordon W Rewcastle, Christina M Buchanan, William A Denny, Peter R Shepherd, Jack U Flanagan
Phosphoinositide 3-kinases (PI3K) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high selectivity and high affinity characteristics found in existing compounds. Molecular docking including the prediction of water-mediated interactions, was used to model interactions between the ligands and the PI3Kα affinity pocket...
May 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28526733/discovery-and-optimization-of-hkt288-a-cadherin-6-targeting-adc-for-the-treatment-of-ovarian-and-renal-cancer
#2
Carl U Bialucha, Scott D Collins, Xiao Li, Parmita Saxena, Xiamei Zhang, Clemens Dürr, Bruno LaFont, Pierric Prieur, Yeonju Shim, Rebecca Mosher, David Lee, Lance Ostrom, Tiancen Hu, Sanela Bilic, Ivana Liric Rajlic, Vladimir Capka, Wei Jiang, Joel P Wagner, GiNell Elliott, Artur Veloso, Jessica C Piel, Meghan M Flaherty, Keith G Mansfield, Emily K Meseck, Tina Rubic-Schneider, Anne Serdakowski London, William R Tschantz, Markus Kurz, Duc Nguyen, Aaron Bourret, Matthew J Meyer, Jason E Faris, Mary J Janatpour, Vivien W Chan, Nicholas C Yoder, Kalli C Catcott, Molly A McShea, Xiuxia Sun, Hui Gao, Juliet Williams, Francesco Hofmann, Jeffrey A Engelman, Seth A Ettenberg, William R Sellers, Emma Lees
Despite an improving therapeutic landscape, significant challenges remain in treating the majority of advanced ovarian and renal cancer patients. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancer. HKT288 is an optimized CDH6-targeting DM4-based antibody drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal anti-tumor activity and highlights CDH6 as a novel antigen for biotherapeutic development...
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28524181/common-pitfalls-in-preclinical-cancer-target-validation
#3
REVIEW
William G Kaelin
An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness...
May 19, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28521657/several-inhibitors-of-the-plk1-polo-box-domain-turn-out-to-be-non-specific-protein-alkylators
#4
Vincent Archambault, Karine Normandin
For almost a decade, there has been much interest in the development of chemical inhibitors of Polo-like kinase 1 (Plk1) protein interactions. Plk1 is a master regulator of the cell division cycle that controls numerous substrates. It is a promising target for cancer drug development. Inhibitors of the kinase domain of Plk1 had some success in clinical trials. However, they are not perfectly selective. In principle, Plk1 can also be inhibited by interfering with its protein interaction domain, the Polo-Box Domain (PBD)...
May 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28521532/new-antivirals-for-the-treatment-of-chronic-hepatitis-b
#5
Vincent Soriano, Pablo Barreiro, Laura Benitez, Jose M Peña, Carmen de Mendoza
Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription...
May 18, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28521327/epigenomics-pharmacoepigenomics-and-personalized-medicine-in-cervical-cancer
#6
Shama Prasada Kabekkodu, Sanjiban Chakrabarty, Supriti Ghosh, Angela Brand, Kapaettu Satyamoorthy
Epigenomics encompasses the study of genome-wide changes in DNA methylation, histone modifications and noncoding RNAs leading to altered transcription, chromatin structure, and posttranscription RNA processing, respectively, resulting in an altered rate of gene expression. The role of epigenetic modifications facilitating human diseases is well established. Previous studies have identified histone and cytosine code during normal and pathological conditions with special emphasis on how these modifications regulate transcriptional events...
May 19, 2017: Public Health Genomics
https://www.readbyqxmd.com/read/28521156/2-oxo-3-4-dihydropyrimido-4-5-d-pyrimidinyl-derivatives-as-new-irreversible-pan-fibroblast-growth-factor-receptor-fgfr-inhibitors
#7
Xueqiang Li, Christopher P Guise, Rana Taghipouran, Yuliana Yosaatmadja, Amir Ashoorzadeh, Woo-Kyong Paik, Christopher J Squire, Shuang Jiang, Jinfeng Luo, Yong Xu, Zheng-Chao Tu, Xiaoyun Lu, Xiaomei Ren, Adam V Patterson, Jeff B Smaill, Ke Ding
A series of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives were designed and synthesized as new irreversible inhibitors of the FGFR family. One of the most promising compounds 2l potently inhibited FGFR1/2/3 with IC50 values of 1.06, 0.84 and 5.38 nM, respectively, whereas its potency against FGFR4 was diminished by an order of magnitude. Compound 2l strongly suppresses the proliferation of FGFR1-amplified H520 non-small cell lung cancer cells, FGFR2-amplified SUM52 breast cancer cells and FGFR3-amplified SW780 bladder cancer cells with low nanomolar IC50 values, but was significantly less potent against four FGFR-negative cancer cell lines, with low micromolar IC50 values...
April 22, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28520410/proteolytically-stable-cyclic-decapeptide-for-breast-cancer-cell-targeting
#8
Yogita Raghuwanshi, Hashem Rajab Etayash, Rania Soudy, Igor Paiva, Afsaneh Lavasanifar, Kamaljit Kaur
Starting with a previously reported linear breast cancer targeting decapeptide WxEAAYQkFL, here we report the synthesis of a novel cyclic peptide analogue cyclicWXEAAYQkFL. The N- to C-terminus amide cyclized peptide with one D-amino acid (k) displayed higher uptake by breast cancer cells, with minimal uptake by the non-cancerous cells compared to the linear peptide with two D-amino acids (x and k), and was stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the cyclic peptide was able to capture breast cancer cells specifically and sense samples with ≥25 cancer cells/mL...
May 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28513279/w09-a-novel-autophagy-enhancer-induces-autophagy-dependent-cell-apoptosis-via-activation-of-the-egfr-mediated-ras-raf1-map2k-mapk1-3-pathway
#9
Pinghu Zhang, Zuguo Zheng, Li Ling, Xiaohui Yang, Ni Zhang, Xue Wang, Maozhi Hu, Yu Xia, Yiwen Ma, Haoran Yang, Yunyi Wang, Hongqi Liu
The EGFR (epidermal growth factor receptor) signaling pathway is frequently deregulated in many malignancies. Therefore, targeting the EGFR pathway is regarded as a promising strategy for anticancer drug discovery. Herein, we identified a 2-amino-nicotinonitrile compound (w09) as a novel autophagy enhancer, which potently induced macroautophagy/autophagy and consequent apoptosis in gastric cancer cells. Mechanistic studies revealed that EGFR-mediated activation of the RAS-RAF1-MAP2K-MAPK1/3 signaling pathway played a critical role in w09-induced autophagy and apoptosis of gastric cancer cells...
May 17, 2017: Autophagy
https://www.readbyqxmd.com/read/28513142/12-13-aziridinyl-epothilones-stereoselective-synthesis-of-trisubstituted-olefinic-bonds-from-methyl-ketones-and-heteroaromatic-phosphonates-and-design-synthesis-and-biological-evaluation-of-potent-antitumor-agents
#10
K C Nicolaou, Derek Rhoades, Yanping Wang, Ruoli Bai, Ernest Hamel, Monette Aujay, Joseph Sandoval, Julia Gavrilyuk
The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a 12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess-Kürti-Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations...
May 17, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28511567/treating-the-chronic-phase-chronic-myeloid-leukemia-patient-which-tki-when-to-switch-and-when-to-stop
#11
Ami B Patel, Brandon W Wilds, Michael W Deininger
With the discovery of imatinib mesylate nearly 20 years ago, tyrosine kinase inhibitors (TKIs) were found to be effective in chronic myeloid leukemia (CML). TKI therapy has since revolutionized the treatment of CML and has served as a paradigm of success for targeted drug therapy in cancer. Several new TKIs for CML have been approved over the last two decades that exhibit improved potency over imatinib and have different off-target profiles, providing options for individualized therapy selection. Areas covered: Current management of chronic phase CML, including guidance on the sequential use of imatinib and newer-generation TKIs and evolving treatment strategies such as TKI discontinuation...
May 17, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28511092/epigenetics-and-immunotherapy-the-current-state-of-play
#12
REVIEW
Jennifer Dunn, Sudha Rao
Cancer cells employ a number of mechanisms to escape immunosurveillance and facilitate tumour progression. The recent explosion of interest in immunotherapy, especially immune checkpoint blockade, is a result of discoveries about the fundamental ligand-receptor interactions that occur between immune and cancer cells within the tumour microenvironment. Distinct ligands expressed by cancer cells engage with cell surface receptors on immune cells, triggering inhibitory pathways (such as PD-1/PD-L1) that render immune cells immunologically tolerant...
May 13, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28508826/genomic-aberrations-in-non-small-cell-lung-cancer-and-their-impact-on-treatment-outcome
#13
REVIEW
Amrallah A Mohammed, Hani El-Tanni, Mohammed A Alsakkaf, Ahmad A Mirza, Tariq Al-Malki Atiah, Arwa Al-Malki Atiah
The therapeutic options of nonsmall cell lung cancer (NSCLC) therapy has been changed since the first discovery of activating epidermal growth factor receptor (EGFR) mutations and the development of specific EGFR tyrosine kinase inhibitors, which resulted in the evolution of "personalized medicine." There are a considerable number of genomic aberrations in NSCLC serving as potential predictive biomarkers and drug targets and still more. We summarized the molecular pathways, potential targets, and possible impact on disease outcome in NSCLC...
January 2017: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/28506743/peptide-modified-nanomedicines-for-targeting-cells-at-the-tumor-microenvironment
#14
Ayelet David
Since their initial discovery more than 30 years ago, tumor-homing peptides have become an increasingly useful tool for targeted delivery of therapeutic and diagnostic agents into tumors. Today, it is well accepted that cells at tumor microenvironment (TME) contributes in many ways to cancer development and progression. Tumor-homing peptide are highly suitable ligands to actively target cells at the TME owing to their small size, low immunogenicity, stability, easy manufacturing and low cost. When conjugated to nanosized medicines (nanomedicines) these ligands can interact specifically with surface receptors expressed on cells in the heterogeneous TME, improve cellular uptake of nanomedicines by target cells, and potentially impair tumor growth and progression...
May 12, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28506582/dual-functional-small-molecule-fluorescent-probes-for-image-guided-estrogen-receptor-specific-targeting-coupled-potent-antiproliferative-potency-for-breast-cancer-therapy
#15
Lu Yang, Zhiye Hu, Junjie Luo, Chu Tang, Silong Zhang, Wentao Ning, Chune Dong, Jian Huang, Xianjun Liu, Hai-Bing Zhou
A strategy by integrating biological imaging into early stages of the drug discovery process can improve our understanding of drug activity during preclinical and clinical study. In this article, we designed and synthesized coumarin-based nonsteroidal type fluorescence ligands for drug-target binding imaging. Among these synthesized compounds, 3e, 3f and 3h showed potent ER binding affinity and 3e (IC50=0.012μM) exhibited excellent ERα antagonistic activity, its antiproliferative potency in breast cancer MCF-7 cells is equipotent to the approved drug tamoxifen...
May 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28504969/metabolic-characterization-and-pathway-analysis-of-berberine-protects-against-prostate-cancer
#16
Xianna Li, Aihua Zhang, Hui Sun, Zhidong Liu, Tianlei Zhang, Shi Qiu, Liang Liu, Xijun Wang
Recent explosion of biological data brings a great challenge for the traditional methods. With increasing scale of large data sets, much advanced tools are required for the depth interpretation problems. As a rapid-developing technology, metabolomics can provide a useful method to discover the pathogenesis of diseases. This study was explored the dynamic changes of metabolic profiling in cells model and Balb/C nude-mouse model of prostate cancer, to clarify the therapeutic mechanism of berberine, as a case study...
April 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28504652/a-smap-in-the-face-for-cancer
#17
Shirish Shenolikar
Observed deficits in protein phosphatase 2A (PP2A) function in a variety of human cancers have stimulated drug discovery efforts aimed at restoring PP2A function to inhibit tumor growth. Work published by Sangodkar et al. in this issue of the JCI describes the characterization of orally available small molecule activators of PP2A (SMAPs). These SMAPs attenuated mitogenic signaling and triggered apoptosis in KRAS-mutant lung cancer cells and inhibited tumor growth in murine models. Tumors with mutations in the SMAP-binding site of the PP2A A subunit displayed resistance to SMAPs...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28504558/nanoformulated-water-soluble-paclitaxel-to-enhance-drug-efficacy-and-reduce-hemolysis-side-effect
#18
Weiting Gu, Jie Chen, Prabir Patra, Xiaoyan Yang, Quanrong Gu, Lingxuan Wei, Jason P Acker, Beihua Kong
Surgery, chemotherapy, and radiotherapy are the three top cancer treatment modalities. Paclitaxel (PTX) is one of the most widely used chemotherapy drugs. However, its clinical applications have been significantly limited due to: (i) serious hemolysis effect of currently available commercial paclitaxel formulations and (ii) its water insolubility. An easy way to deliver paclitaxel by a new nanocarrier system using pluronic copolymers of P123/F68 and Sorbitan monopalmitate (Span 40) was reported in our previous research article...
January 1, 2017: Journal of Biomaterials Applications
https://www.readbyqxmd.com/read/28503089/anticancer-chemodiversity-of-ranunculaceae-medicinal-plants-molecular-mechanisms-and-functions
#19
REVIEW
Da-Cheng Hao, Chun-Nian He, Jie Shen, Pei-Gen Xiao
The buttercup family, Ranunculaceae, comprising more than 2,200 species in at least 62 genera, mostly herbs, has long been used in folk medicine and worldwide ethnomedicine since the beginning of human civilization. Various medicinal phytometabolites have been found in Ranunculaceae plants, many of which, such as alkaloids, terpenoids, saponins, and polysaccharides, have shown anti-cancer activities in vitro and in vivo. Most concerns have been raised for two epiphany molecules, the monoterpene thymoquinone and the isoquinoline alkaloid berberine...
February 2017: Current Genomics
https://www.readbyqxmd.com/read/28502558/identification-of-candidate-biomarkers-that-involved-in-the-epigenetic-transcriptional-regulation-for-detection-gastric-cancer-by-itraq-based-quantitative-proteomic-analysis
#20
Zhen Jiang, Xingwang Sun, Qiong Zhang, Xingli Ji, Qin Yu, Ting Huang, Daogang Chen, Hui Chen, Xiaohan Mei, Linyu Wang, Linyan He, Junhua Fang, Li Hou, Li Wang
BACKGROUND: The sensitivities and specificities of biomarkers for gastric cancer are insufficient for clinical detection, and new diagnostics are therefore urgently required. METHODS: A discovery set of gastric cancer tissues was labeled with iTRAQ reagents, separated using SCX chromatography, and identified using LC-ESI-MS/MS. A validation set of gastric cancer tissues was used to confirm the expression levels of potential markers. RESULTS: The present study detected metastasis-associated protein 2 (MTA2) and Histone deacetylases 1 (HDAC1) proteins that were overexpressed in gastric cancer tissues compared with that in adjacent gastric tissue...
May 11, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
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