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Cell Chemical Biology

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https://www.readbyqxmd.com/read/28807782/modulating-protein-protein-interactions-of-the-mitotic-polo-like-kinases-to-target-mutant-kras
#1
Ana J Narvaez, Suzan Ber, Alex Crooks, Amy Emery, Bryn Hardwick, Estrella Guarino Almeida, David J Huggins, David Perera, Meredith Roberts-Thomson, Roberta Azzarelli, Fiona E Hood, Ian A Prior, David W Walker, Richard Boyce, Robert G Boyle, Samuel P Barker, Christopher J Torrance, Grahame J McKenzie, Ashok R Venkitaraman
Mutations activating KRAS underlie many forms of cancer, but are refractory to therapeutic targeting. Here, we develop Poloppin, an inhibitor of protein-protein interactions via the Polo-box domain (PBD) of the mitotic Polo-like kinases (PLKs), in monotherapeutic and combination strategies to target mutant KRAS. Poloppin engages its targets in biochemical and cellular assays, triggering mitotic arrest with defective chromosome congression. Poloppin kills cells expressing mutant KRAS, selectively enhancing death in mitosis...
July 27, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28781124/potent-and-selective-covalent-quinazoline-inhibitors-of-kras-g12c
#2
Mei Zeng, Jia Lu, Lianbo Li, Frederic Feru, Chunshan Quan, Thomas W Gero, Scott B Ficarro, Yuan Xiong, Chiara Ambrogio, Raymond M Paranal, Marco Catalano, Jay Shao, Kwok-Kin Wong, Jarrod A Marto, Eric S Fischer, Pasi A Jänne, David A Scott, Kenneth D Westover, Nathanael S Gray
Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C...
July 27, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28757181/tumor-organoids-as-a-pre-clinical-cancer-model-for-drug-discovery
#3
REVIEW
Fleur Weeber, Salo N Ooft, Krijn K Dijkstra, Emile E Voest
Tumor organoids are 3D cultures of cancer cells that can be derived on an individual patient basis with a high success rate. This creates opportunities to build large biobanks with relevant patient material that can be used to perform drug screens and facilitate drug development. The high take rate will also allow side-by-side comparison to evaluate the translational potential of this model system to the patient. These tumors-in-a-dish can be established for a variety of tumor types including colorectal, pancreas, stomach, prostate, and breast cancers...
July 27, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28807783/aggregation-and-its-influence-on-the-immunomodulatory-activity-of-synthetic-innate-defense-regulator-peptides
#4
Evan F Haney, Bing Catherine Wu, Kelsey Lee, Ashley L Hilchie, Robert E W Hancock
There is increasing interest in developing cationic host defense peptides (HDPs) and their synthetic derivatives as antimicrobial, immunomodulatory, and anti-biofilm agents. These activities are often evaluated without considering biologically relevant concentrations of salts or serum; furthermore certain HDPs have been shown to aggregate in vitro. Here we examined the effect of aggregation on the immunomodulatory activity of a synthetic innate defense regulator peptide, 1018 (VRLIVAVRIWRR-NH2). A variety of salts and solutes were screened to determine their influence on 1018 aggregation, revealing that this peptide "salts out" of solution in an anion-specific and concentration-dependent manner...
July 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28781125/inside-job-methods-for-delivering-proteins-to-the-interior-of-mammalian-cells
#5
REVIEW
Virginia J Bruce, Brian R McNaughton
Currently, 7 of the top 10 selling drugs are biologics, and all of them are proteins. Their large size, structural complexity, and molecular diversity often results in surfaces capable of potent and selective recognition of receptors that challenge, or evade, traditional small molecules. However, most proteins do not penetrate the lipid bilayer exterior of mammalian cells. This severe limitation dramatically limits the number of disease-relevant receptors that proteins can target and modulate. Given the major role proteins play in modern medicine, and the magnitude of this limitation, it is unsurprising that an enormous amount of effort has been dedicated to overcoming this pesky impediment...
July 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28781126/targeting-mycobacterium-tuberculosis-sensitivity-to-thiol-stress-at-acidic-ph-kills-the-bacterium-and-potentiates-antibiotics
#6
Garry B Coulson, Benjamin K Johnson, Huiqing Zheng, Christopher J Colvin, Robert J Fillinger, Elizabeth R Haiderer, Neal D Hammer, Robert B Abramovitch
Mycobacterium tuberculosis (Mtb) must sense and adapt to immune pressures such as acidic pH during pathogenesis. The goal of this study was to isolate compounds that inhibit acidic pH resistance, thus defining virulence pathways that are vulnerable to chemotherapy. Here, we report that the compound AC2P36 selectively kills Mtb at acidic pH and potentiates the bactericidal activity of isoniazid, clofazimine, and diamide. We show that AC2P36 activity is associated with thiol stress and causes an enhanced accumulation of intracellular reactive oxygen species at acidic pH...
July 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28781123/the-high-affinity-interaction-between-orc-and-dna-that-is-required-for-replication-licensing-is-inhibited-by-2-arylquinolin-4-amines
#7
Nicola J Gardner, Peter J Gillespie, Jamie T Carrington, Emma J Shanks, Stuart P McElroy, Emma J Haagensen, Julie A Frearson, Andrew Woodland, J Julian Blow
In late mitosis and G1, origins of DNA replication must be "licensed" for use in the upcoming S phase by being encircled by double hexamers of the minichromosome maintenance proteins MCM2-7. A "licensing checkpoint" delays cells in G1 until sufficient origins have been licensed, but this checkpoint is lost in cancer cells. Inhibition of licensing can therefore kill cancer cells while only delaying normal cells in G1. In a high-throughput cell-based screen for licensing inhibitors we identified a family of 2-arylquinolin-4-amines, the most potent of which we call RL5a...
July 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28757183/rapid-screening-and-identification-of-living-pathogenic-organisms-via-optimized-bioorthogonal-non-canonical-amino-acid-tagging
#8
Allison Rae Sherratt, Yanouchka Rouleau, Christian Luebbert, Miroslava Strmiskova, Teodor Veres, Sabah Bidawid, Nathalie Corneau, John Paul Pezacki
Pathogenic bacteria can be a major cause of illness from environmental sources as well as the consumption of contaminated products, giving rise to public health concerns globally. The surveillance of such living organisms in food and water supplies remains an important challenge in mitigating their deleterious societal effects. Here, we have developed an optimized bioorthogonal non-canonical amino acid tagging approach to the imaging, capture, and interrogation of shigatoxigenic/verotoxigenic Escherichia coli (VTEC) and Listeria that enables the distinction between living wild-type pathogenic bacteria...
July 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28757182/amine-landscaping-to-maximize-protein-dye-fluorescence-and-ultrastable-protein-ligand-interaction
#9
Michael T Jacobsen, Michael Fairhead, Per Fogelstrand, Mark Howarth
Chemical modification of proteins provides great opportunities to control and visualize living systems. The most common way to modify proteins is reaction of their abundant amines with N-hydroxysuccinimide (NHS) esters. Here we explore the impact of amine number and positioning on protein-conjugate behavior using streptavidin-biotin, a central research tool. Dye-NHS modification of streptavidin severely damaged ligand binding, necessitating development of a new streptavidin-retaining ultrastable binding after labeling...
July 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28736238/the-pursuit-of-therapeutic-biomarkers-with-high-throughput-cancer-cell-drug-screens
#10
REVIEW
Steven P Williams, Ultan McDermott
In the last decade we have witnessed tremendous advances in our understanding of the landscape of the molecular alterations that underpin many of the most prevalent cancers, in the use of automated high-throughput platforms for high-throughput drug screens in cancer cells, in the creation of more clinically relevant cancer cell models, and lastly in the development of more useful computational approaches in the pursuit of biomarkers of drug response. Separately, each of these improvements will undoubtedly lead to improvements in the treatment of cancer patients but to fulfill the promise of truly personalized cancer medicine, we must bring these disciplines together in a truly multidisciplinary fashion...
July 12, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28757184/cell-permeable-stapled-peptide-inhibitor-of-wnt-signaling-that-targets-%C3%AE-catenin-protein-protein-interactions
#11
Laura Dietrich, Bernd Rathmer, Kenneth Ewan, Tanja Bange, Stefan Heinrichs, Trevor C Dale, Dennis Schade, Tom N Grossmann
The Wnt signaling pathway plays a critical role in cell proliferation and differentiation, thus it is often associated with diseases such as cancers. Unfortunately, although attractive, developing anti-cancer strategy targeting Wnt signaling has been challenging given that the most attractive targets are involved in protein-protein interactions (PPIs). Here, we develop a stapled peptide inhibitor that targets the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling...
July 10, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28736239/%C3%AE-trcp1-is-a-vacillatory-regulator-of-wnt-signaling
#12
Marcus John Long, Hong-Yu Lin, Saba Parvez, Yi Zhao, Jesse Richard Poganik, Paul Huang, Yimon Aye
Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the β-catenin-driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox sensors, rendering bolus redox signal-dosing methods uninformative. Herein we examine the ramifications of single-protein target-specific AR upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits β-catenin/Wnt...
July 10, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28648379/targeted-protein-degradation-from-chemical-biology-to-drug-discovery
#13
REVIEW
Philipp M Cromm, Craig M Crews
Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches...
June 10, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28602761/joining-forces-the-chemical-biology-medicinal-chemistry-continuum
#14
REVIEW
Alleyn T Plowright, Christian Ottmann, Michelle Arkin, Yves P Auberson, Henk Timmerman, Herbert Waldmann
The scientific advances being made across all disciplines are creating ever-increasing opportunities to enhance our knowledge of biological systems and how they relate to human disease. One of the central driving forces in discovering new medicines is medicinal chemistry, where the design and synthesis of novel compounds has led to multiple drugs. Chemical biology, sitting at the interface of many disciplines, has now emerged as a major contributor to the understanding of biological systems and is becoming an integral part of drug discovery...
June 1, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28732202/retraction-notice-to-an-atp-competitive-inhibitor-modulates-the-allosteric-function-of-the-her3-pseudokinase
#15
Peter Littlefield, Mark M Moasser, Natalia Jura
No abstract text is available yet for this article.
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28732201/small-molecules-for-early-endosome-specific-patch-clamping
#16
Cheng-Chang Chen, Elisabeth S Butz, Yu-Kai Chao, Yulia Grishchuk, Lars Becker, Stefan Heller, Susan A Slaugenhaupt, Martin Biel, Christian Wahl-Schott, Christian Grimm
To resolve the subcellular distribution of endolysosomal ion channels, we have established a novel experimental approach to selectively patch clamp Rab5 positive early endosomes (EE) versus Rab7/LAMP1-positive late endosomes/lysosomes (LE/LY). To functionally characterize ion channels in endolysosomal membranes with the patch-clamp technique, it is important to develop techniques to selectively enlarge the respective organelles. We found here that two small molecules, wortmannin and latrunculin B, enlarge Rab5-positive EE when combined but not Rab7-, LAMP1-, or Rab11 (RE)-positive vesicles...
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28732200/systematic-metrics-depicting-cell-death-kinetics
#17
Ying Li, Junying Yuan
In a recent issue of Cell Systems, Forcina et al. (2017) developed a scalable time-lapse analysis of cell death kinetics (STACK) method and combined it with a "lag exponential death" model to quantitatively characterize the onset and rate of cell death. STACK provides a useful quantitative tool to determine how cell death kinetics may be modulated pharmacologically in cell culture systems.
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28732199/catch-shiny-droplets-in-suspension-finding-the-needle-in-a-haystack
#18
Nina V Hein-Fuchs, Renate König
In a recent issue of Cell Chemical Biology, Chaipan et al. (2017) described a high-throughput screening methodology to identify epitopes on HIV-1 particles recognized by broadly neutralizing antibodies. The approach utilizes a droplet-based microfluidics platform combining robust phenotypic single-virus sorting with next-generation sequencing of viral quasispecies.
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28732198/primary-cell-phenotypic-screening-illuminates-adrs-and-aops
#19
Audrey J Bone, Keith A Houck
Preclinical, in vitro screening for adverse drug reactions continues to present challenges in the field of drug development. In this issue of Cell Chemical Biology, Shah et al. (2017) employ a phenotypic screening strategy using a panel of human primary cells to define a signature response and an adverse outcome pathway for delayed type IV skin hypersensitivity.
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28732197/wrecking-staph-s-rafts-staphylococcus-aureus-no-longer-unsinkable
#20
Rafi Rashid, Kimberly A Kline
Functional membrane microdomains (FMMs) serve to spatially restrict and coordinate a diversity of cellular functions. Flotillins serve as scaffolds within FMMs, and in this issue of Cell Chemical Biology, Koch et al. (2017) show that disrupting Staphylococcus aureus scaffolds via small molecules perturbs virulence gene expression and attenuates S. aureus virulence.
July 20, 2017: Cell Chemical Biology
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