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Christine A Herdman, Tracy E Strecker, Rajendra P Tanpure, Zhi Chen, Alex Winters, Jeni Gerberich, Li Liu, Ernest Hamel, Ralph P Mason, David J Chaplin, Mary Lynn Trawick, Kevin G Pinney
The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs)...
December 1, 2016: MedChemComm
Narisa Phummarin, Helena I Boshoff, Patricia S Tsang, James Dalton, Siouxsie Wiles, Clifton E Barry Rd, Brent R Copp
A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of Mycobacterium tuberculosis (Mtb). We report the results of a preliminary structure-activity relationship (SAR) study of the compound class which has yielded more potent inhibitors. An Mtb cytochrome bd oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the qcrB gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (bc1) complex, were resistant to the library...
November 1, 2016: MedChemComm
C H Castaneda, M J Scuderi, T G Edwards, G D Harris, C M Dupureur, K J Koeller, C Fisher, J K Bashkin
We report the synthesis of two novel pyrrole-imidazole polyamides with N-terminal guanidinium or tetramethylguanidinium groups and evaluate their antiviral activity against three cancer-causing human papillomavirus strains. Introduction of guanidinium improves antiviral activity when compared to an unsubstituted analog, especially in IC90 values. These substitutions change DNA-binding preferences, while binding affinity remains unchanged.
November 1, 2016: MedChemComm
Barbara Zdrazil, Eva Hellsberg, Michael Viereck, Gerhard F Ecker
Retrieval of congeneric and consistent SAR data sets for protein targets of interest is still a laborious task to do if no appropriate in-house data set is available. However, combining integrated open data sources (such as the Open PHACTS Discovery Platform) with workflow tools now offers the possibility of querying across multiple domains and tailoring the search to the given research question. Starting from two phylogenetically related protein targets of interest (the human serotonin and dopamine transporters), the whole chemical compound space was explored by implementing a scaffold-based clustering of compounds possessing biological measurements for both targets...
September 14, 2016: MedChemComm
Ryan P Murelli, Michael P D'Erasmo, Danielle R Hirsch, Christine Meck, Takashi Masaoka, Jennifer A Wilson, Baofeng Zhang, Rajat K Pal, Emilio Gallicchio, John A Beutler, Stuart F J Le Grice
HIV Reverse Transcriptase-associated ribonuclease H activity is a promising enzymatic target for drug development that has not been successfully targeted in the clinic. While the α-hydroxytropolone-containing natural products β-thujaplicinol and manicol have emerged as some of the most potent leads described to date, structure-function studies have been limited to the natural products and semi-synthetic derivatives of manicol. Thus, a library of α-hydroxytropolones synthesized through a convenient oxidopyrylium cycloaddition/ring-opening sequence have been tested in in vitro and cell-based assays, and have been analyzed using computational support...
September 1, 2016: MedChemComm
Michael P D'Erasmo, Takashi Masaoka, Jennifer A Wilson, Errol M Hunte, John A Beutler, Stuart F J Le Grice, Ryan P Murelli
α-Hydroxytropolones are established inhibitors of several therapeutically relevant binuclear metalloenzymes, and thus lead drug targets for various human diseases. We have leveraged a recently-disclosed three-component oxidopyrylium cycloaddition in the first solid-phase synthesis of α-hydroxytropolones. We also showed that, while minor impurities exist after cleavage and aqueous wash, the semi-crude products display activity in HIV RT-associated RNaseH enzymatic and cell-based assays consistent with pure molecules made in solution phase...
September 1, 2016: MedChemComm
H Ü Kaniskan, M S Eram, J Liu, D Smil, M L Martini, Y Shen, V Santhakumar, P J Brown, C Arrowsmith, M Vedadi, J Jin
Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I protein arginine methyltransferase (PRMT) that catalyzes the conversion of arginine into monomethylarginine (MMA) and further into asymmetric dimethylarginine (ADMA). CARM1 methylates histone 3 arginines 17 and 26, as well as numerous non-histone proteins including CBP/p300, SRC-3, NCOA2, PABP1, and SAP49, while also functioning as a coactivator for various proteins that have been linked to cancer such as p53, NF-κβ, β-catenin, E2F1 and steroid hormone receptor ERα...
September 1, 2016: MedChemComm
C Granchi, S Fortunato, F Minutolo
The altered metabolism observed in cancer cells generally consists in increased glucose uptake and glycolytic activity. This is associated with an overexpression of glucose transporter proteins (GLUTs), which facilitate glucose uptake across the plasma membrane and play a crucial role in the survival of cancer cells. Therefore GLUTs are considered as suitable targets for the treatment of cancer. Herein we review some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents...
September 1, 2016: MedChemComm
Jesse A Jones, Kristopher G Virga, Giuseppe Gumina, Kirk E Hevener
This review discusses next-generation antibacterial agents developed using rational, or targeted, drug design strategies. The focus of this review is on small-molecule compounds that have been designed to bypass developing bacterial resistance, improve the antibacterial spectrum of activity, and/or to optimize other properties, including physicochemical and pharmacokinetic properties. Agents are discussed that affect known antibacterial targets, such as the bacterial ribosome, nucleic acid binding proteins, and proteins involved in cell-wall biosynthesis; as well as some affecting novel bacterial targets which do not have currently marketed agents...
September 1, 2016: MedChemComm
Carl S Rye, Nicola E A Chessum, Scott Lamont, Kurt G Pike, Paul Faulder, Julie Demeritt, Paul Kemmitt, Julie Tucker, Lorenzo Zani, Matthew D Cheeseman, Rosie Isaac, Louise Goodwin, Joanna Boros, Florence Raynaud, Angela Hayes, Alan T Henley, Emmanuel de Billy, Christopher J Lynch, Swee Y Sharp, Robert Te Poele, Lisa O' Fee, Kevin M Foote, Stephen Green, Paul Workman, Keith Jones
Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay...
August 1, 2016: MedChemComm
Yu Li, Guiquan Xia, Qi Guo, Li Wu, Shizhen Chen, Zhigang Yang, Wei Wang, Zhong-Yin Zhang, Xin Zhou, Zhong-Xing Jiang
Fluorine is a highly attractive element for both medicinal chemistry and imaging technologies. To facilitate protein tyrosine phosphatases (PTPs)-targeted drug discovery and imaging-guided PTP research with fluorine, several highly potent and (19)F MR sensitive PTP inhibitors were discovered through a structure-based focused library strategy.
August 1, 2016: MedChemComm
Huy X Ngo, Sylvie Garneau-Tsodikova, Keith D Green
Fungal infections directly affect millions of people each year. In addition to the invasive fungal infections of humans, the plants and animals that comprise our primary food source are also susceptible to diseases caused by these eukaryotic microbes. The need for antifungals, not only for our medical needs, but also for use in agriculture and livestock causes a high demand for novel antimycotics. Herein, we provide an overview of the most commonly used antifungals in medicine and agriculture. We also present a summary of the recent progress (from 2010-2016) in the discovery/development of new agents against fungal strains of medical/agricultural relevance, as well as information related to their biological activity, their mode(s) of action, and their mechanism(s) of resistance...
July 1, 2016: MedChemComm
Jessica E Wynn, Wenyu Zhang, Denis M Tebit, Laurie R Gray, Marie-Louise Hammarskjold, David Rekosh, Webster L Santos
High throughput screening of a 4096 compound library of boronic acid and acridine containing branched peptides revealed compounds that have dissociation constants in the low nanomolar regime for HIV-1 RRE IIB RNA. We demonstrate that branched peptide boronic acids A5, A6, and A7 inhibit the production of p24, an HIV-1 capsid protein, in a dose-dependent manner.
July 1, 2016: MedChemComm
D Digles, B Zdrazil, J-M Neefs, H Van Vlijmen, C Herhaus, A Caracoti, J Brea, B Roibás, M I Loza, N Queralt-Rosinach, L I Furlong, A Gaulton, L Bartek, S Senger, C Chichester, O Engkvist, C T Evelo, N I Franklin, D Marren, G F Ecker, E Jacoby
Phenotypic screening is in a renaissance phase and is expected by many academic and industry leaders to accelerate the discovery of new drugs for new biology. Given that phenotypic screening is per definition target agnostic, the emphasis of in silico and in vitro follow-up work is on the exploration of possible molecular mechanisms and efficacy targets underlying the biological processes interrogated by the phenotypic screening experiments. Herein, we present six exemplar computational protocols for the interpretation of cellular phenotypic screens based on the integration of compound, target, pathway, and disease data established by the IMI Open PHACTS project...
June 1, 2016: MedChemComm
Claire Colas, Peter Man-Un Ung, Avner Schlessinger
The human Solute Carrier (SLC) transporters are important targets for drug development. Structure-based drug discovery for SLC transporters requires the description of their structure, dynamics, and mechanism of interaction with small molecule ligands and ions. The recent determination of atomic structures of human SLC transporters and their homologs, combined with improved computational power and prediction methods have led to an increased applicability of structure-based drug design methods for human SLC members...
June 1, 2016: MedChemComm
Kyle V Butler, Kelsey Bohn, Christine A Hrycyna, Jian Jin
Activating mutations of human K-Ras proteins are among the most common oncogenic mutations, present in approximately 30% of all human cancers. Posttranslational modifications to K-Ras guide it to the plasma membrane and disruption of this localization inhibits the growth of Ras-driven cancers. The human isoprenylcysteine carboxyl methyltransferase (hIcmt) enzyme catalyzes the final α-carboxyl methylesterification of the C-terminal farnesyl cysteine of K-Ras, which is necessary for its proper localization. Thus, hIcmt inhibition is a regarded as a promising cancer therapy...
May 1, 2016: MedChemComm
Reji N Nair, Jitendra K Mishra, Fangzheng Li, Mariola Tortosa, Chunying Yang, Joanne R Doherty, Michael Cameron, John L Cleveland, William R Roush, Thomas D Bannister
Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an amino acid transporter recognition element was shown to augment anti-tumour efficacy vs. Raji cells. Amino acid conjugation also improves the pharmacodynamic properties of experimental MCT1/2 inhibitors...
May 1, 2016: MedChemComm
Paul N Black, Constance Ahowesso, David Montefusco, Nipun Saini, Concetta C DiRusso
The fatty acid transport proteins (FATP) are classified as members of the Solute Carrier 27 (Slc27) family of proteins based on their ability to function in the transport of exogenous fatty acids. These proteins, when localized to the plasma membrane or at intracellular membrane junctions with the endoplasmic reticulum, function as a gate in the regulated transport of fatty acids and thus represent a therapeutic target to delimit the acquisition of fatty acids that contribute to disease as in the case of fatty acid overload...
April 1, 2016: MedChemComm
Stefan G Kathman, Alexander V Statsyuk
Covalent probes and drugs have found widespread use as research tools and clinical agents. Covalent probes are useful because of their increased intracellular potency and because covalent labeling of cellular proteins can be tracked using click chemistry. Covalent drugs, on the other hand, can overcome drug resistance toward their reversible counterparts. The discovery of covalent probes and drugs usually follows two trajectories: covalent natural products and their analogues are used directly as covalent probes or drugs; or alternatively, a non-covalent probe is equipped with a reactive group and converted into a covalent probe...
April 1, 2016: MedChemComm
Tobias Linder, Harald Bernsteiner, Priyanka Saxena, Florian Bauer, Thomas Erker, Eugen Timin, Steffen Hering, Anna Stary-Weinzinger
Inhibition of hERG K(+) channels by structurally diverse drugs prolongs the ventricular action potential and increases the risk of torsade de pointes arrhythmias and sudden cardiac death. The capture of drugs behind closed channel gates, so-called drug trapping, is suggested to harbor an increased pro-arrhythmic risk. In this study, the trapping mechanisms of a trapped hERG blocker propafenone and a bulky derivative (MW: 647.24 g mol(-1)) were studied by making use of electrophysiological measurements in combination with molecular dynamics simulations...
March 1, 2016: MedChemComm
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