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Receptors And Lead Compound

Jia Ke, Qi Lu, Xin Wang, Rui Sun, Zhe Jin, Xiaoyi Zhan, Jianshu Hu, David Chi-Cheong Wan, Chun Hu
The epidermal growth factor receptors (EGFRs), in which overexpression (known as upregulation) or overactivity have been associated with a number of cancers, has become an attractive molecular target for the treatment of selective cancers. We report here the design and synthesis of a novel series of 4,5-dihydro-1 H -thieno [2',3':2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives and the screening for their inhibitory activity on the EGFR high-expressing human A549 cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)...
August 8, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Mariana A Ribeiro, Molly S Estill, Geysson J Fernandez, Leonardo N Moraes, Stephen A Krawetz, Wellerson R Scarano
Male fertility and spermatogenesis are directly linked to the Sertoli cell's ability to produce factors associated with germ cell development. Sertoli cells express receptors for FSH and testosterone, and are the major regulators of spermatogenesis. Recent studies report that regulatory RNA molecules, such as microRNAs (miRNAs), are able to modulate testicular function during spermatogenesis and that their altered expression may be involved in male infertility. miRNAs may play a role in the response to xenobiotics that have an adverse consequences to health...
August 7, 2018: Toxicology
Frank Narjes, Yafeng Xue, Stefan von Berg, Jesper Malmberg, Antonio Llinas, Roine I Olsson, Johan Jirholt, Hanna Grindebacke, Agnes Leffler, Nafizal Hossain, Matti Lepistö, Linda Thunberg, Hanna Leek, Anna Aagaard, Jane McPheat, Eva L Hansson, Elisabeth Back, Stefan Tångefjord, Rongfeng Chen, Yao Xiong, Ge Hongbin, Thomas Hansson
Retinoic acid receptor-related orphan receptor γt (RORγt), has been identified as the master regulator of TH 17 cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small molecule approach. Herein we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray co-crystal structures. Efforts in targeting the co-factor recruitment site from the 4-aryl group on the thiophene led to a series of potent binders, with nanomolar activity in a primary human TH 17 cell assay...
August 10, 2018: Journal of Medicinal Chemistry
Lena Heinbockel, Günther Weindl, Guillermo Martinez-de-Tejada, Wilmar Correa, Susana Sanchez-Gomez, Sergio Bárcena-Varela, Torsten Goldmann, Patrick Garidel, Thomas Gutsmann, Klaus Brandenburg
The most potent cell wall-derived inflammatory toxins ("pathogenicity factors") of Gram-negative and -positive bacteria are lipopolysaccharides (LPS) (endotoxins) and lipoproteins (LP), respectively. Despite the fact that the former signals via toll-like receptor 4 (TLR4) and the latter via TLR2, the physico-chemistry of these compounds exhibits considerable similarity, an amphiphilic molecule with a polar and charged backbone and a lipid moiety. While the exterior portion of the LPS (i.e., the O-chain) represents the serologically relevant structure, the inner part, the lipid A, is responsible for one of the strongest inflammatory activities known...
2018: Frontiers in Immunology
Tomoya Yamada
Rodent carcinogenicity studies are useful for screening for human carcinogens but they are not perfect. Some modes of action (MOAs) lead to cancers in both experimental rodents and humans, but others that lead to cancers in rodents do not do so in humans. Therefore, analysing the MOAs by which chemicals produce tumours in rodents and determining the relevance of such tumour data for human risk are critical. Recently, experimental data were obtained as case examples of an evaluation of the human relevance of pyrethroid (metofluthrin and momfluorothrin)- and pyrethrins-induced liver tumours in rats based on MOA...
July 1, 2018: Toxicology Research
Georgia Melagraki, Evangelos Ntougkos, Dimitra Papadopoulou, Vagelis Rinotas, Georgios Leonis, Eleni Douni, Antreas Afantitis, George Kollias
An in silico drug discovery pipeline for the virtual screening of plant-origin natural products (NPs) was developed to explore new direct inhibitors of TNF and its close relative receptor activator of nuclear factor kappa-B ligand (RANKL), both representing attractive therapeutic targets for many chronic inflammatory conditions. Direct TNF inhibition through identification of potent small molecules is a highly desired goal; however, it is often hampered by severe limitations. Our approach yielded a priority list of 15 NPs as potential direct TNF inhibitors that were subsequently tested in vitro against TNF and RANKL...
2018: Frontiers in Pharmacology
Angela Balistrieri, Laura Hobohm, Trisha Srivastava, Angela Meier, Ross Corriden
Bisphenol-A is a synthetic organic compound frequently present in consumer plastics, including plastic-lined cans, water bottles, toys, and teeth sutures. Previous studies have shown that BPA can produce adverse health effects that include defects in reproductive function and altered prenatal/childhood development. However, little is known regarding the effects of BPA on immune function. In this study, we assessed the effect of BPA on human neutrophils, a critical component of the innate immune system's defense against pathogens...
August 8, 2018: American Journal of Physiology. Cell Physiology
Johnny Nagasawa, Steven Govek, Mehmet Kahraman, Andiliy Lai, Celine Bonnefous, Karensa Douglas, John Sensintaffar, Nhin Lu, Kyoungjin Lee, Anna Aparicio, Josh Kaufman, Jing Qian, Gang Shao, Rene Prudente, James D Joseph, Beatrice Darimond, Daniel Brigham, Kate Maheu, Richard Heyman, Peter Rix, Jeffrey H Hager, Nicholas D Smith
Approximately eighty percent of breast cancers are estrogen receptor alpha (ER-) positive, and although women typically initially respond well to anti-hormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-, and is active in patients who have progressed on anti-hormonal agents. However fulvestrant suffers from poor pharmaceutical properties and must be administered by intra-muscular injections that limit the total amount of drug that can be administered, and hence lead to the potential for incomplete receptor blockade...
August 7, 2018: Journal of Medicinal Chemistry
Yiji Liao, Kexin Xu
Epigenetics is the main mechanism that controls transcription of specific genes with no changes in the underlying DNA sequences. Epigenetic alterations lead to abnormal gene expression patterns that contribute to carcinogenesis and persist throughout disease progression. Because of the reversible nature, epigenetic modifications emerge as promising anticancer drug targets. Several compounds have been developed to reverse the aberrant activities of enzymes involved in epigenetic regulation, and some of them show encouraging results in both preclinical and clinical studies...
August 7, 2018: Asian Journal of Andrology
Eilidh K Leitch, Nagarajan Elumalai, Maria Fridén-Saxin, Göran Dahl, Paul Wan, Paul Clarkson, Eric Valeur, Garry Pairaudeau, Helen Boyd, Ali Tavassoli
Cellular uptake of circulating cholesterol occurs via the low density lipoprotein receptor (LDLR). The E3 ubiquitin ligase IDOL is a mediator of LDLR degradation, with IDOL homodimerization thought to be required for its activity. To probe the possibility of modulating LDLR levels with an inhibitor of IDOL homodimerization, we screened a SICLOPPS library of 3.2 million cyclic peptides for compounds that disrupt this protein-protein interaction. We identified cyclo -CFFLYT as the lead inhibitor, and improved its activity through the incorporation of non-natural amino acids...
July 21, 2018: Chemical Science
T V Ajay Kumar, Alias Anand S Athavan, C Loganathan, K Saravanan, S Kabilan, V Parthasathy
Transforming growth factor-β (TGF-β) family members plays a vital role in regulating hormonal function, bone formation, tissue remodeling, and erythropoiesis, cell growth and apoptosis. TGF-β super-family members mediate signal transduction via serine/threonine kinase receptors located on the cell membrane. Variation in expression of the TGF-β type I and II receptors in the cancer cells compromise its tumor suppressor activities which direct to oncogenic functions. The present study was aimed to screen the potent TGF-β type I inhibitors through atom based 3D-QSAR and pharmacophore modelling...
July 24, 2018: Computational Biology and Chemistry
George S Amato, Amruta Manke, Vineetha Vasukuttan, Robert W Wiethe, Rodney W Snyder, Scott P Runyon, Rangan Maitra
Antagonists of peripheral type 1 cannabinoid receptors (CB1) may have utility in the treatment of obesity, liver disease, metabolic syndrome and dyslipidemias. We have targeted analogues of the purine inverse agonist otenabant (1) for this purpose. The non-tissue selective CB1 antagonist rimonabant (2) was approved as a weight-loss agent in Europe but produced centrally mediated adverse effects in some patients including dysphoria and suicidal ideation leading to its withdrawal. Efforts are now underway to produce compounds with limited brain exposure...
July 27, 2018: Bioorganic & Medicinal Chemistry
Zhen Wang, Yali Zhang, Daniel Pinkas, Alice Fox, Jinfeng Luo, Huocong Huang, Shengyang Cui, Qiuping Xiang, Tingting Xu, Qiuju Xun, Dongsheng Zhu, Zheng-Chao Tu, Xiaomei Ren, Rolf A Brekken, Alex N Bullock, Guang Liang, Ke Ding, Xiaoyun Lu
Discoidin domain receptor 1 and 2 (DDR1 and DDR2) are new potential targets for anti-inflammatory drug discovery. A series of heterocycloalkynylbenzimides were designed and optimized to co-inhibit DDR1 and DDR2. One of the most promising compounds, 5n, tightly bound to DDR1 and DDR2 protein with Kd values of 7.9 and 8.0 nM, and potently inhibited the kinases with IC50 values of 9.4 and 20.4 nM, respectively, while was significantly less potent for a panel of 403 wild-type kinases at 1.0 μM. DDR1 and DDR2 kinase inhibition by 5n was validated by Western blotting analysis in primary human lung fibroblasts...
August 3, 2018: Journal of Medicinal Chemistry
Damilola Dawodu, Margret Patecki, Jan Hegermann, Inna Dumler, Hermann Haller, Yulia Kiyan
Resorptive activity of osteoclasts is important for maintaining bone homeostasis. Endogenous compounds such as oxidized low density lipoprotein (oxLDL) have been shown to disturb this activity. While some studies have investigated the effects of oxLDL on the process of osteoclastogenesis, the underlying mechanism are not fully understood. We show here that oxLDL concentrations of ~10-25 µg protein (0.43-1.0 µM MDA/mg protein) completely blocked the formation of functional osteoclasts. The underlying mechanism implies an inhibition of autophagy that in turn leads to a decreased fusion of cathepsin K (CatK)-loaded lysosomal vesicles with the ruffled border membrane...
August 2, 2018: Scientific Reports
Tanis D Godwin, S Thomas Kelly, Tom P Brew, Nicola M Bougen-Zhukov, Andrew B Single, Augustine Chen, Cassie E Stylianou, Lawrence D Harris, Sophie K Currie, Bryony J Telford, Henry G Beetham, Gary B Evans, Michael A Black, Parry J Guilford
BACKGROUND: The E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer, and germline mutations predispose to the cancer syndrome Hereditary Diffuse Gastric Cancer. We are taking a synthetic lethal approach to identify druggable vulnerabilities in CDH1-mutant cancers. METHODS: Density distributions of cell viability data from a genome-wide RNAi screen of isogenic MCF10A and MCF10A-CDH1-/- cells were used to identify protein classes affected by CDH1 mutation...
July 31, 2018: Gastric Cancer
Zahra Haghighijoo, Zahra Rezaei, Mansooreh Jaberipoor, Samaneh Taheri, Meysam Jani, Soghra Khabnadideh
Quinazoline is one of the most widespread scaffolds amongst natural and synthetic bioactive compounds. Recently the quinazoline derivatives and in particular the 4-anilinoquinazolines have attracted much attention for their anticancer properties due to their capability to stabilize the kinase activity of epidermal growth factor receptor (EGFR). A series of fifteen previously designed and synthesized 4-anilinoquinazoline analogs (4-18) were evaluated for cytotoxic activity on two breast cancer cell lines (MCF-7 and MDA-MB-468)...
August 2018: Research in Pharmaceutical Sciences
Victoria Casado-Medrano, Martin J Baker, Cynthia Lopez-Haber, Mariana Cooke, Shaofei Wang, Maria J Caloca, Marcelo G Kazanietz
The family of Rho GTPases are involved in the dynamic control of cytoskeleton reorganization and other fundamental cellular functions, including growth, motility, and survival. Rac1, one of the best characterized Rho GTPases, is an established effector of receptors and an important node in signaling networks crucial for tumorigenesis and metastasis. Rac1 hyperactivation is common in human cancer and could be the consequence of overexpression, abnormal upstream inputs, deregulated degradation, and/or anomalous intracellular localization...
July 31, 2018: Biochemical Society Transactions
Xin Wu, Ethan N W Howe, Philip A Gale
Transmembrane anion transport has been the focus of a number of supramolecular chemistry research groups for a number of years. Much of this research is driven by the biological relevance of anion transport and the search to find new treatments for diseases such as cystic fibrosis, which is caused by genetic problems leading to faulty cystic fibrosis transmembrane conductance regulator (CFTR) channels, which in turn lead to reduced chloride and bicarbonate transport through epithelial cell membranes. Considerable effort has been devoted to the development of new transporters, and our group along with others have been searching for combinations of organic scaffolds and anion binding groups that produce highly effective transporters that work at low concentration...
July 31, 2018: Accounts of Chemical Research
Kazeem O Sulaiman, Temitope U Kolapo, Abdulmujeeb T Onawole, Ataul Islam, Rukayat O Adegoke, Suaibu O Badmus
Ebola virus (EBOV) is a lethal human pathogen with a risk of global spread of its zoonotic infections, and Ebolavirus Zaire specifically has the highest fatality rate amongst other species. There is a need for continuous effort towards having therapies, as a single licensed treatment to neutralize the EBOV is yet to come into reality. This present study virtually screened the MCULE database containing almost 36 million compounds against the structure of a Zaire Ebola viral protein (VP) 35 and a consensus scoring of both MCULE and CLCDDW docking programs remarked five compounds as potential hits...
July 30, 2018: Journal of Biomolecular Structure & Dynamics
Huy H Nguyen, Michelle Bora Kim, Robert J Wilson, Christopher Butch, Katie M Kuo, Eric J Miller, Yesim A Tahirovic, Edgars Jecs, Valarie M Truax, Tao Wang, Chi Sum, Mary Ellen Cvijic, Gretchen M Schroeder, Lawrence J Wilson, Dennis C Liotta
CXCR4 is a G protein-coupled receptor that interacts with its cognate ligand CXCL12 to synchronize many physiological responses and pathological processes. Disruption of the CXCL12-CXCR4 circuitry by small molecule antagonists has emerged as a promising strategy for cancer intervention. We previously disclosed a hit-to-lead effort that led to the discovery of a series of tetrahydroisoquinoline-based CXCR4 antagonists exemplified by the lead compound TIQ15. Herein, we describe our medicinal chemistry efforts toward the redesign of TIQ15 as a result of high mouse microsomal clearance, potent CYP2D6 inhibition, and poor membrane permeability...
July 27, 2018: Journal of Medicinal Chemistry
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