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Targetted small molecules

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https://www.readbyqxmd.com/read/28431342/discovery-of-tetrahydrocarbazoles-as-dual-perk-and-prb-inhibitors
#1
Mahesh R Kulkarni, Madhav S Mane, Usha Ghosh, Rajiv Sharma, Nitin P Lad, Ankita Srivastava, Asha Kulkarni-Almeida, Prashant S Kharkar, Vijay M Khedkar, Shivaji S Pandit
The extracellular signal-regulated kinase (ERK) is one of the most important molecular targets for cancer that controls diverse cellular processes such as proliferation, survival, differentiation and motility. Similarly, the Rb (retinoblastoma protein) is a tumor suppressor protein and its function is to prevent excessive cell growth by inhibiting cell cycle progression. When the cell is ready to divide, pRb is phosphorylated, becomes inactive and allows cell cycle progression. Herein, we discovered a new series of tetrahydrocarbazoles as dual inhibitors of pERK and pRb phosphorylation...
March 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28431259/allosteric-regulation-of-metabolism-in-cancer-endogenous-mechanisms-and-considerations-for-drug-design
#2
REVIEW
Jamie A Macpherson, Dimitrios Anastasiou
Alterations in metabolic processes have been linked to various diseases, including cancer. Although gene expression can dictate long-term metabolic adaptation, many metabolic changes found in cancer are associated with altered allosteric properties of the underlying enzymes. Small molecule-protein interactions and intracellular signalling converge to orchestrate these allosteric mechanisms, which, emerging evidence suggests, constitute a promising therapeutic avenue. In this review we focus on glucose and energy metabolism to illustrate the role of allostery in cancer physiology and we discuss approaches to streamline the process of targeting aberrant allosteric pathways with small molecules...
April 18, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28431213/genome-mining-unearths-a-hybrid-nonribosomal-peptide-synthetase-like-pteridine-synthase-biosynthetic-gene-cluster
#3
Hyun Bong Park, Corey E Perez, Karl W Barber, Jesse Rinehart, Jason M Crawford
Nonribosomal peptides represent a large class of metabolites with pharmaceutical relevance. Pteridines, such as pterins, folates, and flavins, are heterocyclic metabolites that often serve as redox-active cofactors. The biosynthetic machineries for construction of these distinct classes of small molecules operate independently in the cell. Here, we discovered an unprecedented nonribosomal peptide synthetase-like-pteridine synthase hybrid biosynthetic gene cluster in Photorhabdus luminescens using genome synteny analysis...
March 15, 2017: ELife
https://www.readbyqxmd.com/read/28431169/spa-ln-a-scoring-function-of-ligand-nucleic-acid-interactions-via-optimizing-both-specificity-and-affinity
#4
Zhiqiang Yan, Jin Wang
Nucleic acids have been widely recognized as potential targets in drug discovery and aptamer selection. Quantifying the interactions between small molecules and nucleic acids is critical to discover lead compounds and design novel aptamers. Scoring function is normally employed to quantify the interactions in structure-based virtual screening. However, the predictive power of nucleic acid-ligand scoring functions is still a challenge compared to other types of biomolecular recognition. With the rapid growth of experimentally determined nucleic acid-ligand complex structures, in this work, we develop a knowledge-based scoring function of nucleic acid-ligand interactions, namely SPA-LN...
April 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28430857/repurposed-drugs-targeting-eif2%C3%AE-p-mediated-translational-repression-prevent-neurodegeneration-in-mice
#5
Mark Halliday, Helois Radford, Karlijn A M Zents, Collin Molloy, Julie A Moreno, Nicholas C Verity, Ewan Smith, Catharine A Ortori, David A Barrett, Martin Bushell, Giovanna R Mallucci
Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss...
April 19, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28430357/reactive-oxygen-species-key-regulators-in-vascular-health-and-diseases
#6
REVIEW
Qishan Chen, Qiwen Wang, Jianhua Zhu, Qingzhong Xiao, Li Zhang
Reactive oxygen species (ROS) are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. In the vascular system, physiological levels of ROS are essential for normal vascular functions including endothelial homeostasis and smooth muscle cell contraction. In contrast, uncontrolled overproduction of ROS resulted from imbalance of ROS generation and elimination, leads to the development of vascular diseases. Excessive ROS cause vascular cell damages, recruitment of inflammatory cells, lipid peroxidation, activation of metalloproteinases, and deposition of extracellular matrix, collectively leading to vascular remodeling...
April 21, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28429938/high-resolution-accurate-mass-mass-spectrometry-enables-in-depth-characterization-of-in-vivo-biotransformations-for-intact-antibody-drug-conjugates
#7
Jintang He, Dian Su, Carl K Ng, Luna Liu, Shang-Fan Yu, Thomas H Pillow, Geoffrey Del Rosario, Martine Darwish, Byoung-Chul Lee, Rachana Ohri, Hongxiang Zhou, Xueji Wang, Jiawei Lu, Surinder Kaur, Keyang Xu
Antibody-drug conjugates (ADCs) represent a promising class of therapeutics for the targeted delivery of highly potent cytotoxic drugs to tumor cells to improve bioactivity while minimizing side effects. ADCs are composed of both small and large molecules, and therefore have complex molecular structures. In vivo biotransformations may further increase the complexity of ADCs, representing a unique challenge for bioanalytical assays. Quadrupole time-of-flight mass spectrometry (Q-TOF MS) with electrospray ionization has been widely used for characterization of intact ADCs...
April 21, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28429674/targeting-the-role-of-lipoprotein-a-in-stroke
#8
Mahdi Garelnabi, Zahra Mazhar, Andrew Hughes
Stroke is the third leading cause of death in the United States, behind only heart disease and cancer, with over 140,000 associated deaths per year. Considerable research is ongoing to examine the role of modifiable risk factors which may cause or contribute to a stroke occurring. Although age and family history are generally considered to be major risk factors, there are several modifiable and non-modifiable risk factors that are linked to the pathogenesis of a stroke. Lipoprotein (a), or Lp(a), is a type of low-density lipoprotein containing an integral apoB100 component with an attached ApoA1 isoform via a disulfide linkage...
April 21, 2017: Cardiovascular & Hematological Disorders Drug Targets
https://www.readbyqxmd.com/read/28428276/micellar-delivery-of-mir-34a-modulator-rubone-and-paclitaxel-in-resistant-prostate-cancer
#9
Di Wen, Yang Peng, Feng Lin, Rakesh K Singh, Ram I Mahato
Treatment of prostate cancer with paclitaxel (PTX) often fails due to development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that co-delivery of PTX and 2'-hydroxy-2,4,4',5,6'-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes PTX-resistant prostate cancer cells, killing both cancer stem-like cells (CSCs) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28428274/egfr-mediates-responses-to-small-molecule-drugs-targeting-oncogenic-fusion-kinases
#10
Aria Vaishnavi, Laura Schubert, Uwe Rix, Lindsay A Marek, Anh T Le, Stephen Keysar, Magdalena J Glogowska, Matthew A Smith, Severine L Kako, Natalia J Sumi, Kurtis D Davies, Kathryn E Ware, Marileila Varella-Garcia, Eric B Haura, Antonio Jimeno, Lynn E Heasley, Dara L Aisner, Robert C Doebele
Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28428272/hur-small-molecule-inhibitor-elicits-differential-effects-in-adenomatosis-polyposis-and-colorectal-carcinogenesis
#11
Michaela Lang, David Berry, Katharina Passecker, Ildiko Mesteri, Sabin Bhuju, Florian Ebner, Vitaly Sedlyarov, Rayko Evstatiev, Kyle Dammann, Alexander Loy, Orest Kuzyk, Pavel Kovarik, Vineeta Khare, Martin Beibel, Guglielmo Roma, Nicole Meisner-Kober, Christoph Gasche
HuR is an RNA-binding protein implicated in immune homeostasis and various cancers, including colorectal cancer. HuR binding to AU-rich elements within the 3' untranslated region of mRNAs encoding oncogenes, growth factors, and various cytokines leads message stability and translation. In this study, we evaluated HuR as a small-molecule target for preventing colorectal cancer in high-risk groups such as those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). In human specimens, levels of cytoplasmic HuR were increased in colonic epithelial cells from patients with IBD, IBD-cancer, FAP-adenoma, and colorectal cancer, but not in patients with IBD-dysplasia...
February 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28428246/key-features-of-an-hsp70-chaperone-allosteric-landscape-revealed-by-ion-mobility-native-mass-spectrometry-and-double-electron-electron-resonance
#12
Alex L Lai, Eugenia M Clerico, Mandy E Blackburn, Nisha A Patel, Carol V Robinson, Peter P Borbat, Jack H Freed, Lila M Gierasch
Proteins are dynamic entities that populate conformational ensembles, and most functions of proteins depend on their dynamic character. Allostery, in particular, relies on ligand-modulated shifts in these conformational ensembles. Hsp70s are allosteric molecular chaperones with conformational landscapes that involve large rearrangements of their two domains (viz, the nucleotide-binding domain and substrate-binding domain) in response to adenine nucleotides and substrates. However, it remains unclear how the Hsp70 conformational ensemble is populated at each point of the allosteric cycle and how ligands control these populations...
April 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28428051/cell-penetrating-peptide-cgkrk-mediates-efficient-and-widespread-targeting-of-bladder-mucosa-following-focal-injury
#13
James I Griffin, Siu Kit Kevin Cheng, Tomoko Hayashi, Dennis Carson, Manju Saraswathy, Devatha P Nair, Dmitri Simberg
The bladder presents an attractive target for topical drug delivery. The barrier function of the bladder mucosa (urothelium) presents a penetration challenge for small molecules and nanoparticles. We found that focal mechanical injury of the urothelium greatly enhances the binding and penetration of intravesically-administered cell-penetrating peptide CGKRK (Cys-Gly-Lys-Arg-Lys). Notably, the CGKRK bound to the entire urothelium, and the peptide was able to penetrate into the muscular layer. This phenomenon was not dependent on intravesical bleeding and was not caused by an inflammatory response...
April 17, 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/28427184/kpnb1-mediated-nuclear-import-is-required-for-motility-and-inflammatory-transcription-factor-activity-in-cervical-cancer-cells
#14
Tamara Stelma, Virna D Leaner
Karyopherin β1 is a nuclear import protein involved in the transport of proteins containing a nuclear localisation sequence. Elevated Karyopherin β1 expression has been reported in cancer and transformed cells and is essential for cancer cell proliferation and survival. Transcription factors such as NFĸB and AP-1 contain a nuclear localisation sequence and initiate the expression of multiple factors associated with inflammation and cancer cell biology. Our study investigated the effect of inhibiting nuclear import via Karyopherin β1 on cancer cell motility and inflammatory signaling using siRNA and the novel small molecule, Inhibitor of Nuclear Import-43, INI-43...
March 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427012/label-free-electrochemical-biosensing-of-small-molecule-inhibition-on-o-glcnac-glycosylation
#15
Yu Yang, Yuxin Gu, Bin Wan, Xiaomin Ren, Liang-Hong Guo
O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) plays a critical role in modulating protein function in many cellular processes and human diseases such as Alzheimer's disease and type II diabetes, and has emerged as a promising new target. Specific inhibitors of OGT could be valuable tools to probe the biological functions of O-GlcNAcylation, but a lack of robust nonradiometric assay strategies to detect glycosylation, has impeded efforts to identify such compounds. Here we have developed a novel label-free electrochemical biosensor for the detection of peptide O-GlcNAcylation using protease-protection strategy and electrocatalytic oxidation of tyrosine mediated by osmium bipyridine as a signal reporter...
April 12, 2017: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/28426978/visualizing-spatial-distribution-of-small-molecules-in-the-rhubarb-stalk-rheum-rhabarbarum-by-surface-transfer-mass-spectrometry-imaging
#16
Joanna Nizioł, Justyna Sekuła, Tomasz Ruman
Laser desorption/ionization mass spectrometry imaging (LDI-MSI) with gold nanoparticle-enhanced target (AuNPET) was used for visualization of small molecules in the rhubarb stalk (Rheum rhabarbarum L.). Analysis was focused on spatial distribution of biologically active compounds which are found in rhubarb species. Detected compounds belong to a very wide range of chemical compound classes such as anthraquinone derivatives and their glucosides, stilbenes, anthocyanins, flavonoids, polyphenols, organic acids, chromenes, chromanones, chromone glycosides and vitamins...
April 17, 2017: Phytochemistry
https://www.readbyqxmd.com/read/28426808/a-screen-for-protective-drugs-against-delayed-hypoxic-injury
#17
Chun-Ling Sun, Huiliang Zhang, Meng Liu, Wang Wang, C Michael Crowder
Despite longstanding efforts to develop cytoprotective drugs against ischemia/reperfusion (IR) injuries, there remains no effective therapeutics to treat hypoxic injury. The failure of traditional strategies at solving this problem suggests the need for novel and unbiased approaches that can lead to previously unsuspected targets and lead compounds. Towards this end, we report here a unique small molecule screen in the nematode C. elegans for compounds that improve recovery when applied after the hypoxic insult, using a C...
2017: PloS One
https://www.readbyqxmd.com/read/28426667/bioenergetic-status-modulates-motor-neuron-vulnerability-and-pathogenesis-in-a-zebrafish-model-of-spinal-muscular-atrophy
#18
Penelope J Boyd, Wen-Yo Tu, Hannah K Shorrock, Ewout J N Groen, Roderick N Carter, Rachael A Powis, Sophie R Thomson, Derek Thomson, Laura C Graham, Anna A L Motyl, Thomas M Wishart, J Robin Highley, Nicholas M Morton, Thomas Becker, Catherina G Becker, Paul R Heath, Thomas H Gillingwater
Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles...
April 20, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28425525/exploiting-hydrogen-bonding-interactions-to-probe-smaller-linear-and-cyclic-diamines-binding-to-g-quadruplexes-a-dft-and-molecular-dynamics-study
#19
Mrinal Kanti Si, Anik Sen, Bishwajit Ganguly
G-quadruplexes are formed by the association of four guanine bases through Hoogsteen hydrogen bonding in guanine-rich sequences of DNA and exist in the telomere as well as in promoter regions of certain oncogenes. The sequences of G-quadruplex-DNA are targets for the design of molecules that can bind and can be developed as anti-cancer drugs. The linear and cyclic protonated diamines have been explored to bind to G-quadruplex-DNA through hydrogen bonding interactions. The quadruplex-DNA binders exploit π-stacking and hydrogen bonding interactions with the phosphate backbone of loops and grooves...
April 20, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28425495/the-biglen-gpr171-peptide-receptor-system-within-the-basolateral-amygdala-regulates-anxiety-like-behavior-and-contextual-fear-conditioning
#20
Erin N Bobeck, Ivone Gomes, Darlene Pena, Kirstie A Cummings, Roger L Clem, Mihaly Mezei, Lakshmi A Devi
Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and other mood disorders. Since GPR171, a recently deorphanized receptor for the abundant neuropeptide BigLEN, is expressed in the BLA, we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds. One of the hits, MS0021570_1, was identified as a GPR171 antagonist based on its ability to block (i) BigLEN-mediated activation of GPR171 in heterologous cells, (ii) BigLEN-mediated hyperpolarization of BLA pyramidal neurons, and (iii) feeding induced by DREADD-mediated activation of BigLEN containing AgRP neurons in the arcuate nucleus...
April 20, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
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