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Targetted small molecules

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https://www.readbyqxmd.com/read/28549348/ocular-toxicities-associated-with-targeted-anticancer-agents-an-analysis-of-clinical-data-with-management-suggestions
#1
Chen Fu, Dan S Gombos, Jared Lee, Goldy C George, Kenneth Hess, Andrew Whyte, David S Hong
Ocular toxicities are among the most common adverse events resulting from targeted anticancer agents and are becoming increasingly relevant in the management of patients on these agents. The purpose of this study is to provide a framework for management of these challenging toxicities based on objective data from FDA labels and from analysis of the literature. All oncologic drugs approved by the FDA up to March 14, 2015, were screened for inclusion. A total of 16 drugs (12 small-molecule drugs and 4 monoclonal antibodies) were analyzed for ocular toxicity profiles based on evidence of ocular toxicity...
May 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28549259/purinergic-2x7-receptor-activation-regulates-wnt-signaling-in-human-mandibular-derived-osteoblasts
#2
Pimrumpai Rochanakit Sindhavajiva, Panunn Sastravaha, Mansuang Arksornnukit, Prasit Pavasant
OBJECTIVE: Purinergic 2X7 receptor (P2X7R) activation modulates in vitro mineralization by primary rat and human osteoblasts. However, the detailed mechanism of how P2X7R activation affects primary human osteoblasts remains unclear. The aim of this study was to investigate the effect of P2X7R activation on human mandibular-derived osteoblast (hMOB) differentiation. DESIGN: Primary human osteoblasts were obtained from non-pathologic mandibular bone from healthy patients...
May 18, 2017: Archives of Oral Biology
https://www.readbyqxmd.com/read/28548834/subtly-modulating-glycogen-synthase-kinase-3-%C3%AE-allosteric-inhibitors-development-and-their-potential-for-the-treatment-of-chronic-diseases
#3
Valle Palomo, Daniel I Pérez, Carlos Roca, Cara Anderson, Natalia Rodriguez-Muela, Concepción Pérez, Jose A Morales-Garcia, Julio A Reyes, Nuria E Campillo, Ana M Pérez-Castillo, Lee L Rubin, Lubov T Timchenko, Carmen Gil, Ana Martínez
Glycogen synthase kinase 3 β (GSK-3β) is a central target in several unmet diseases. To increase the specificity of GSK-3β inhibitors in chronic treatments we are developing small molecules allowing subtle modulation of GSK-3β activity. Design synthesis, structure-activity relationships and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3β are here presented. Furthermore, we show how allosteric binders may overcome the β-catenin side effects associated to strong GSK-3β inhibition...
May 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28547797/vitamin-d-receptor-agonists-regulate-ocular-developmental-angiogenesis-and-modulate-expression-of-dre-mir-21-and-vegf
#4
Stephanie L Merrigan, Breandán N Kennedy
BACKGROUND AND PURPOSE: Pathological growth of ocular vasculature networks can underpin visual impairment in neovascular age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. Our aim was to uncover novel pharmacological regulators of ocular angiogenesis by phenotype-based screening in zebrafish. EXPERIMENTAL APPROACH: A bioactive chemical library of 465 drugs was screened to identify small molecule inhibitors of ocular hyaloid vasculature (HV) angiogenesis in zebrafish larvae...
May 26, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28547736/rice-bran-metabolome-contains-amino-acids-vitamins-cofactors-and-phytochemicals-with-medicinal-and-nutritional-properties
#5
Iman Zarei, Dustin G Brown, Nora Jean Nealon, Elizabeth P Ryan
BACKGROUND: Rice bran is a functional food that has shown protection against major chronic diseases (e.g. obesity, diabetes, cardiovascular disease and cancer) in animals and humans, and these health effects have been associated with the presence of bioactive phytochemicals. Food metabolomics uses multiple chromatography and mass spectrometry platforms to detect and identify a diverse range of small molecules with high sensitivity and precision, and has not been completed for rice bran...
December 2017: Rice
https://www.readbyqxmd.com/read/28546917/challenges-in-the-delivery-of-therapies-to-melanoma-brain-metastases
#6
Gautham Gampa, Shruthi Vaidhyanathan, Brynna-Wilken Resman, Karen E Parrish, Svetomir N Markovic, Jann N Sarkaria, William F Elmquist
Brain metastases are a major cause of morbidity and mortality in patients with advanced melanoma. Recent approval of several molecularly-targeted agents and biologics has brought hope to patients with this previously untreatable disease. However, patients with symptomatic melanoma brain metastases have often been excluded from pivotal clinical trials. This may be in part attributed to the fact that several of the approved small molecule molecularly-targeted agents are substrates for active efflux at the blood-brain barrier, limiting their effective delivery to brain metastases...
December 2016: Current Pharmacology Reports
https://www.readbyqxmd.com/read/28546431/disruption-of-mitochondrial-electron-transport-chain-function-potentiates-the-pro-apoptotic-effects-of-mapk-inhibition
#7
Andrew P Trotta, Jesse D Gelles, Madhavika N Serasinghe, Patrick Loi, Jack L Arbiser, Jerry E Chipuk
The mitochondrial network is a major site of ATP production through the coupled integration of the electron transport chain (ETC) with oxidative phosphorylation. In melanoma, arising from the Val600Glu mutation in the kinase v-RAF murine sarcoma viral oncogene homolog B (BRAFV600E), oncogenic signaling enhances glucose-dependent metabolism, while reducing mitochondrial ATP production. Likewise, when BRAFV600E is pharmacologically inhibited by targeted therapies (e.g. PLX-4032/Vemurafenib), glucose metabolism is reduced and cells increase mitochondrial ATP production to sustain survival...
May 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28546333/microdosing-drug-development-of-small-organic-and-protein-therapeutics
#8
Mats L Bergstrom
Microdosing as a regulatory concept was introduced to facilitate explorative studies in humans, using very low doses for plasma PK assessment with highly sensitive read-out or for imaging studies with radionuclide-labelled compounds. The bearing principle was that at these low doses, with limited exposure in limited time periods and in well controlled small populations, the risk of adverse effect is low. This regulation included specifications on a reduced pre-clinical toxicity assessment package making the route to human studies more rapid and cheap...
May 25, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28546144/midostaurin-approved-for-flt3-mutated-aml
#9
Mark Levis
Midostaurin was recently approved by the U.S. Food and Drug Administration for the treatment of FLT3-mutant acute myeloid leukemia (AML). This is the first drug to receive regulatory approval for AML in the U.S. since the year 2000. Midostaurin is a small molecule kinase inhibitor with activity against the receptor tyrosine kinase FLT3, and its approval will hopefully mark the beginning of an era of targeted agents for the treatment of molecularly-defined subtypes of AML.
May 25, 2017: Blood
https://www.readbyqxmd.com/read/28545975/quinazolinone-derivatives-as-inhibitors-of-homologous-recombinase-rad51
#10
Ambber Ward, Lilong Dong, Jonathan M Harris, Kum Kum Khanna, Fares Al-Ejeh, David P Fairlie, Adrian P Wiegmans, Ligong Liu
RAD51 is a vital component of the homologous recombination DNA repair pathway and is overexpressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). A proposed strategy for improving therapeutic outcomes for patients is through small molecule inhibition of RAD51, thereby sensitizing tumor cells to DNA damaging irradiation and/or chemotherapy. Here we report structure-activity relationships for a library of quinazolinone derivatives. A novel RAD51 inhibitor (17) displays up to 15-fold enhanced inhibition of cell growth in a panel of TNBC cell lines compared to compound B02, and approximately 2-fold increased inhibition of irradiation-induced RAD51 foci formation...
May 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28545966/third-strand-stabilization-of-poly-u-poly-a-poly-u-triplex-by-the-naturally-occurring-flavone-luteolin-a-multi-spectroscopic-approach
#11
Richa Tiwari, Lucy Haque, Sutanwi Bhuiya, Suman Das
Naturally occurring flavonoid luteolin (LTN) was found to interact with double stranded poly(A).poly(U) and triple stranded poly(U).poly(A)*poly(U) with association constants of the order of 10(4)M(-1). The association was monitored by various spectroscopic and viscometric techniques. Non-cooperative binding was observed for the association of LTN with two different polymorphic forms of RNA. Intercalation mode of binding was confirmed by fluorescence quenching and viscometric experiments. Thermal melting profiles indicated greater stabilization of the Hoogsteen base paired third strand (∼16°C) compared to Watson-Crick double strand (∼5°C) of RNA by LTN...
May 22, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28545714/anticystogenic-activity-of-a-small-molecule-pak4-inhibitor-may-be-a-novel-treatment-for-autosomal-dominant-polycystic-kidney-disease
#12
Vicki J Hwang, Xia Zhou, Xiaonan Chen, Josephine Trott, Omran Abu Aboud, Kyuhwan Shim, Lai Kuan Dionne, Kenneth J Chmiel, William Senapedis, Erkan Baloglu, Moe R Mahjoub, Xiaogang Li, Robert H Weiss
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common hereditary renal disease with no currently available targeted therapies. Based on the established connection between β-catenin signaling and renal ciliopathies, and on data from our and other laboratories showing striking similarities of this disease and cancer, we evaluated the use of an orally bioavailable small molecule, KPT-9274 (a dual inhibitor of the protein kinase PAK4 and nicotinamide phosphoribosyl transferase), for treatment of ADPKD...
May 23, 2017: Kidney International
https://www.readbyqxmd.com/read/28544567/chemoproteomics-aided-medicinal-chemistry-for-the-discovery-of-epha2-inhibitors
#13
Stephanie Heinzlmeir, Jonas Lohse, Tobias Treiber, Denis Kudlinzki, Verena Linhard, Santosh Lakshmi Gande, Sridhar Sreeramulu, Krishna Saxena, Xiaofeng Liu, Mathias Wilhelm, Harald Schwalbe, Bernhard Kuster, Guillaume Médard
The receptor tyrosine kinase EPHA2 has gained interest as therapeutic drug target in cancer and infectious diseases. However, EPHA2 research and EPHA2-based therapies have been hampered by the lack of selective small molecule inhibitors. Here, we report on the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor Dasatinib as a lead structure. We designed hybrid structures of Dasatinib and the previously known EPHA2 binders CHEMBL249097, PD-173955 and a known EPHB4 inhibitor in order to exploit both the ATP pocket entrance as well as the ribose pocket as binding epitopes in the kinase EPHA2...
May 24, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28544542/conditional-macrophage-depletion-increases-inflammation-and-does-not-inhibit-the-development-of-osteoarthritis-in-obese-mafia-mice
#14
Chia-Lung Wu, Jenna McNeill, Kelsey Goon, Dianne Little, Kelly Kimmerling, Janet Huebner, Virginia Kraus, Farshid Guilak
OBJECTIVE: Macrophages are believed to play a critical role in the inflammation associated with the development of osteoarthritis (OA) in obesity. The objective of the study was to investigate whether short-term, systemic depletion of macrophages would mitigate OA following injury in obese mice. METHODS: CSF-1R-GFP(+) Macrophage Fas-Induced Apoptosis (MaFIA) transgenic mice that allow conditional depletion of macrophages were placed on a high-fat diet and underwent surgery to induce knee OA...
May 23, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28544466/simultaneous-imaging-of-endogenous-survivin-mrna-and-on-demand-drug-release-in-live-cells-by-using-a-mesoporous-silica-nanoquencher
#15
Peiyan Yuan, Xin Mao, Kok Chan Chong, Jiaqi Fu, Sijun Pan, Shuizhu Wu, Changmin Yu, Shao Q Yao
The design of multifunctional drug delivery systems capable of simultaneous target detection, imaging, and therapeutics in live mammalian cells is critical for biomedical research. In this study, by using mesoporous silica nanoparticles (MSNs) chemically modified with a small-molecule dark quencher, followed by sequential drug encapsulation, MSN capping with a dye-labeled antisense oligonucleotide, and bioorthogonal surface modification with cell-penetrating poly(disulfide)s, the authors have successfully developed the first mesoporous silica nanoquencher (qMSN), characterized by high drug-loading and endocytosis-independent cell uptake, which is able to quantitatively image endogenous survivin mRNA and release the loaded drug in a manner that depends on the survivin expression level in tumor cells...
May 24, 2017: Small
https://www.readbyqxmd.com/read/28544401/induced-fit-recognition-of-ccg-trinucleotide-repeats-by-a-nickel-chromomycin-complex-results-in-large-scale-dna-deformation
#16
Wen-Hsuan Tseng, Chung-Ke Chang, Pei-Ching Wu, Nien-Jen Hu, Gene-Hsiang Lee, Ching-Cherng Tzeng, Stephen Neidle, Ming-Hon Hou
Small-molecule compounds targeting trinucleotide repeats in DNA have considerable potential as therapeutic or diagnostic agents against many neurological diseases. NiII(Chro)2 (Chro = chromomycin A3) was found to bind specifically to the minor groove of (CCG)n repeats in duplex DNA, with unique fluorescence features that may serve as a probe for disease detection. Crystallographic studies have revealed that the specificity originates from the large-scale spatial rearrangement of the DNA structure, including extrusion of consecutive bases and backbone distortions, with a sharp bending of the duplex accompanied by conformational changes in the Ni(II) chelate itself...
May 23, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28544137/phenotypic-identification-of-a-novel-autophagy-inhibitor-chemotype-targeting-lipid-kinase-vps34
#17
Herbert Waldmann, Lucas Robke, Luca Laraia, Marjorie A Carnero Corrales, Georgios Konstantinidis, Makoto Muroi, André Richters, Michael Winzker, Tobias Engbring, Stefano Tomassi, Nobumoto Watanabe, Hiroyuki Osada, Daniel Rauh, Yaowen Wu, Julian Engel
Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring formation of autophagy-induced puncta indicating accumulation of lipidated cytosolic protein LC3 on the autophagosomal membrane...
May 22, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28544095/phenotypic-assays-for-mycobacterium-tuberculosis-infection
#18
Ok-Ryul Song, Nathalie Deboosere, Vincent Delorme, Christophe J Queval, Gaspard Deloison, Elisabeth Werkmeister, Frank Lafont, Alain Baulard, Raffaella Iantomasi, Priscille Brodin
Tuberculosis (TB) is still a major global threat, killing more than one million persons each year. With the constant increase of Mycobacterium tuberculosis strains resistant to first- and second-line drugs, there is an urgent need for the development of new drugs to control the propagation of TB. Although screenings of small molecules on axenic M. tuberculosis cultures were successful for the identification of novel putative anti-TB drugs, new drugs in the development pipeline remains scarce. Host-directed therapy may represent an alternative for drug development against TB...
May 19, 2017: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
https://www.readbyqxmd.com/read/28542923/the-polysialic-acid-mimetics-idarubicin-and-irinotecan-stimulate-neuronal-survival-and-neurite-outgrowth-and-signal-via-protein-kinase-c
#19
Gabriele Loers, Steven Astafiev, Yuliya Hapiak, Vedangana Saini, Bibhudatta Mishra, Sheraz Gul, Gurcharan Kaur, Melitta Schachner, Thomas Theis
Polysialic acid (PSA) is a large, negatively charged, linear homopolymer of alpha2-8-linked sialic acid residues. It is generated by two polysialyltransferases and attached to N- and/or O-linked glycans, and its main carrier is the neural cell adhesion molecule NCAM. PSA controls the development and regeneration of the nervous system by enhancing cell migration, axon pathfinding, synaptic targeting, synaptic plasticity, by regulating the differentiation of progenitor cells and by modulating cell-cell and cell-matrix adhesions...
May 24, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28542609/potent-and-selective-inhibition-of-pathogenic-viruses-by-engineered-ubiquitin-variants
#20
Wei Zhang, Ben A Bailey-Elkin, Robert C M Knaap, Baldeep Khare, Tim J Dalebout, Garrett G Johnson, Puck B van Kasteren, Nigel J McLeish, Jun Gu, Wenguang He, Marjolein Kikkert, Brian L Mark, Sachdev S Sidhu
The recent Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola and Zika virus outbreaks exemplify the continued threat of (re-)emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV) encode deubiquitinating (DUB) enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) from cellular proteins to suppress host antiviral innate immune responses...
May 18, 2017: PLoS Pathogens
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