Targeting conformational plasticity of protein kinases.

abstract：:The genetic code specifies 20 common amino acids and is largely preserved in both single and multicellular organisms. Unnatural amino acids (Uaas) have been genetically incorporated into proteins by using engineered orthogonal tRNA/aminoacyl-tRNA synthetase (RS) pairs, enabling new research capabilities and precision ...

journal_title：ACS chemical biology

authors： Parrish AR,She X,Xiang Z,Coin I,Shen Z,Briggs SP,Dillin A,Wang L

更新日期：2012-07-20 00:00:00

abstract：:Combination therapies that enhance efficacy or permit reduced dosages to be administered have seen great success in a variety of therapeutic applications. More fundamentally, the discovery of epistatic pathway interactions not only informs pharmacologic intervention but can be used to better understand the underlying ...

journal_title：ACS chemical biology

authors： Severyn B,Liehr RA,Wolicki A,Nguyen KH,Hudak EM,Ferrer M,Caldwell JS,Hermes JD,Li J,Tudor M

更新日期：2011-12-16 00:00:00

abstract：:The gibberellin (GA) phytohormones are produced not only by plants but also by fungi and bacteria. Previous characterization of a cytochrome P450 (CYP)-rich GA biosynthetic operon found in many symbiotic, nitrogen-fixing rhizobia led to the elucidation of bacterial GA biosynthesis and implicated GA9 as the final produ...

journal_title：ACS chemical biology

authors： Nett RS,Contreras T,Peters RJ

更新日期：2017-04-21 00:00:00

abstract：:The plant hormone auxin is a master regulator of plant growth and development. By regulating rates of cell division and elongation and triggering specific patterning events, indole 3-acetic acid (IAA) regulates almost every aspect of plant development. The perception of auxin involves the formation of a ternary comple...

journal_title：ACS chemical biology

authors： Hayashi K,Neve J,Hirose M,Kuboki A,Shimada Y,Kepinski S,Nozaki H

更新日期：2012-03-16 00:00:00

abstract：:The use of nitric oxide (NO) as a signal for biofilm dispersal has been shown to increase the susceptibility of many biofilms to antibiotics, promoting their eradication. The delivery of NO to biofilms can be achieved by using NO donors with different kinetics and properties of NO release that can influence their effi...

journal_title：ACS chemical biology

authors： Poh WH,Barraud N,Guglielmo S,Lazzarato L,Rolando B,Fruttero R,Rice SA

更新日期：2017-08-18 00:00:00

abstract：:An attractive approach for developing therapeutic peptides is to enhance binding to their targets by stabilizing their α-helical conformation, for example, stabilized BimBH3 peptides (BimSAHB) designed to induce apoptosis. Unexpectedly, we found that such modified peptides have reduced affinity for their targets, the ...

journal_title：ACS chemical biology

authors： Okamoto T,Zobel K,Fedorova A,Quan C,Yang H,Fairbrother WJ,Huang DC,Smith BJ,Deshayes K,Czabotar PE

更新日期：2013-02-15 00:00:00

abstract：:Phenotypic screening of compound libraries is a significant trend in drug discovery, yet success can be hindered by difficulties in identifying the underlying cellular targets. Current approaches rely on tethering bioactive compounds to a capture tag or surface to allow selective enrichment of interacting proteins for...

journal_title：ACS chemical biology

authors： Ohana RF,Kirkland TA,Woodroofe CC,Levin S,Uyeda HT,Otto P,Hurst R,Robers MB,Zimmerman K,Encell LP,Wood KV

更新日期：2015-10-16 00:00:00

abstract：:A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis...

journal_title：ACS chemical biology

authors： Zhu Z,Shaginian A,Grady LC,O'Keeffe T,Shi XE,Davie CP,Simpson GL,Messer JA,Evindar G,Bream RN,Thansandote PP,Prentice NR,Mason AM,Pal S

更新日期：2018-01-19 00:00:00

abstract：:The publication of the first high-resolution crystal structure of a eukaryotic Cys-loop receptor, GluClα, has provided valuable structural information on this important class of ligand-gated ion channels (LGIC). However, limited functional data exist for the GluCl receptors. Before applying the structural insights fro...

journal_title：ACS chemical biology

authors： Daeffler KN,Lester HA,Dougherty DA

更新日期：2014-10-17 00:00:00

abstract：:Mutations that constitutively activate the phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, including alterations in PI3K, PTEN, and AKT, are found in a variety of human cancers, implicating the PI3K lipid kinase as an attractive target for the development of therapeutic agents to treat cancer and other relate...

journal_title：ACS chemical biology

authors： Xie P,Williams DS,Atilla-Gokcumen GE,Milk L,Xiao M,Smalley KS,Herlyn M,Meggers E,Marmorstein R

更新日期：2008-05-16 00:00:00

abstract：:Nephronectin is an extracellular matrix protein that interacts with the α8β1 integrin receptor and plays a role in tissue and organ development, though the motifs that mediate adhesion to the receptor remain unclear. This paper describes the use of self-assembled monolayers to study the adhesion of α8β1-presenting cel...

journal_title：ACS chemical biology

authors： Sánchez-Cortés J,Mrksich M

更新日期：2011-10-21 00:00:00

abstract：:Angiogenesis, the formation of new blood vessels, is implicated in a number of important human diseases, including cancer, diabetic retinopathy, and rheumatoid arthritis. To identify clinically useful angiogenesis inhibitors, we assembled and screened a library of mostly Food and Drug Administration-approved drugs for...

journal_title：ACS chemical biology

authors： Chong CR,Xu J,Lu J,Bhat S,Sullivan DJ Jr,Liu JO

更新日期：2007-04-24 00:00:00

abstract：:Small molecules are widely used in chemical biology without complete knowledge of their target profile, at risk of deriving conclusions that ignore potential confounding effects from unknown off-target interactions. The prediction and further experimental confirmation of novel affinities for PJ34 on Pim1 (IC(50) = 3.7...

journal_title：ACS chemical biology

authors： Antolín AA,Jalencas X,Yélamos J,Mestres J

更新日期：2012-12-21 00:00:00

abstract：:Deubiquitinating enzymes play an important role in a plethora of therapeutically relevant processes and are emerging as pioneering drug targets. Herein, we present a novel probe, Ubiquitin Specific Protease (USP) inhibitor, alongside an alkyne-tagged activity-based probe analogue. Activity-based proteome profiling ide...

journal_title：ACS chemical biology

authors： Ward JA,McLellan L,Stockley M,Gibson KR,Whitlock GA,Knights C,Harrigan JA,Jacq X,Tate EW

更新日期：2016-12-16 00:00:00

abstract：:Although protein kinase inhibitors present excellent pharmaceutical opportunities, lack of selectivity and associated therapeutic side effects are common. Bisubstrate-based inhibitors targeting both the high-selectivity peptide substrate binding groove and the high-affinity ATP pocket address this. However, they are t...

journal_title：ACS chemical biology

authors： van Wandelen LT,van Ameijde J,Ismail-Ali AF,van Ufford HC,Vijftigschild LA,Beekman JM,Martin NI,Ruijtenbeek R,Liskamp RM

更新日期：2013-07-19 00:00:00

abstract：:The perturbation of protein kinases with small organic molecules is a powerful approach to dissect kinase function in complex biological systems. Covalent kinase inhibitors that target thiols in the ATP binding pocket of the kinase domain proved to be ideal reagents for the investigation of highly dynamic cellular pro...

journal_title：ACS chemical biology

authors： Koch A,Rode HB,Richters A,Rauh D,Hauf S

更新日期：2012-04-20 00:00:00

abstract：:A strategy has been established for the synthesis of a family of bifunctional HIV-1 inhibitor covalent conjugates with the potential to bind simultaneously to both the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein trimeric complex (Env). One component of the conjugates is derived from BNM-III-170, a small...

journal_title：ACS chemical biology

authors： Gaffney A,Nangarlia A,Ang CG,Gossert S,Rashad Ahmed AA,Hossain MA,Abrams CF,Smith AB 3rd,Chaiken I

更新日期：2021-01-15 00:00:00

abstract：:Reporter gene assays (RGAs) are commonly used to measure biological pathway modulation by small molecules. Understanding how such compounds interact with the reporter enzyme is critical to accurately interpret RGA results. To improve our understanding of reporter enzymes and to develop optimal RGA systems, we investig...

journal_title：ACS chemical biology

authors： Ho PI,Yue K,Pandey P,Breault L,Harbinski F,McBride AJ,Webb B,Narahari J,Karassina N,Wood KV,Hill A,Auld DS

更新日期：2013-05-17 00:00:00

abstract：:One-third of all human cancers harbor somatic RAS mutations. This leads to aberrant activation of downstream signaling pathways involving the RAF kinases. Current ATP-competitive RAF inhibitors are active in cancers with somatic RAF mutations, such as BRAF(V600) mutant melanomas. However, they paradoxically promote th...

journal_title：ACS chemical biology

authors： Molzan M,Kasper S,Röglin L,Skwarczynska M,Sassa T,Inoue T,Breitenbuecher F,Ohkanda J,Kato N,Schuler M,Ottmann C

更新日期：2013-09-20 00:00:00

abstract：:In a process called quorum sensing, bacteria produce and secrete certain signaling compounds (called autoinducers) that bind to receptors on other bacteria and activate transcription of certain genes. A clever genetic selection yields a new quorum-sensing transcriptional regulator that marches to the beat of a differe...

journal_title：ACS chemical biology

authors： Winans SC

更新日期：2006-08-22 00:00:00

abstract：:The clinical application of siRNA is limited largely by the lack of efficient, cell-specific delivery systems. Antibodies are attractive delivery vehicles for targeted therapy due to their high specificity. In this study we describe the use of a humanized monoclonal antibody (mAb), hu3S193, against Lewis-Y (Le(y)), as...

journal_title：ACS chemical biology

authors： Ma Y,Kowolik CM,Swiderski PM,Kortylewski M,Yu H,Horne DA,Jove R,Caballero OL,Simpson AJ,Lee FT,Pillay V,Scott AM

更新日期：2011-09-16 00:00:00

abstract：:Hypoxia induces a complex circuit of gene expression that drives tumor progression and increases drug resistance. Defining these changes allows for an understanding of how hypoxia alters tumor biology and informs design of lead therapeutics. We probed the role of microRNA-544 (miR-544), which silences mammalian target...

journal_title：ACS chemical biology

authors： Haga CL,Velagapudi SP,Strivelli JR,Yang WY,Disney MD,Phinney DG

更新日期：2015-10-16 00:00:00

abstract：:3-Oxo-β-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-β-sultam inhibitors ...

journal_title：ACS chemical biology

authors： Carvalho LAR,Almeida VT,Brito JA,Lum KM,Oliveira TF,Guedes RC,Gonçalves LM,Lucas SD,Cravatt BF,Archer M,Moreira R

更新日期：2020-04-17 00:00:00

abstract：:The molecular chaperone Hsp90 requires the assistance of immunophilins, co-chaperones, and partner proteins for the conformational maturation of client proteins. Hsp90 inhibition represents a promising anticancer strategy due to the dependence of numerous oncogenic signaling pathways upon Hsp90 function. Historically,...

journal_title：ACS chemical biology

authors： Hall JA,Kusuma BR,Brandt GE,Blagg BS

更新日期：2014-04-18 00:00:00

abstract：:Activation by glycosaminoglycans (GAGs) is an emerging trend among extracellular proteases important in disease. ProMMP-7, the zymogen of a matrix metalloproteinase secreted by mucosal epithelial and tumor cells, is activated at their surfaces by sulfated GAGs, but how? ProMMP-7 is activated in trans by representative...

journal_title：ACS chemical biology

authors： Fulcher YG,Sanganna Gari RR,Frey NC,Zhang F,Linhardt RJ,King GM,Van Doren SR

更新日期：2014-04-18 00:00:00

abstract：:The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-α isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, ...

journal_title：ACS chemical biology

authors： Chowdhury R,Candela-Lena JI,Chan MC,Greenald DJ,Yeoh KK,Tian YM,McDonough MA,Tumber A,Rose NR,Conejo-Garcia A,Demetriades M,Mathavan S,Kawamura A,Lee MK,van Eeden F,Pugh CW,Ratcliffe PJ,Schofield CJ

更新日期：2013-07-19 00:00:00

abstract：:Signal transducer and activator of transcription (STAT) proteins have important biological functions; however, deregulation of STAT signaling is a driving force behind the onset and progression of inflammatory diseases and cancer. While their biological roles suggest that STAT proteins would be valuable targets for de...

journal_title：ACS chemical biology

authors： Attarha S,Reithmeier A,Busker S,Desroses M,Page BDG

更新日期：2020-07-17 00:00:00

abstract：:Botulinum neurotoxins (BoNTs) are the most potent toxins known to man and a significant threat as weapons of bioterrorism. BoNTs contain a metalloprotease domain that blocks neurotransmitter release in nerve terminals, resulting in a descending, flaccid paralysis with a 5-10% mortality rate. Existing treatment options...

journal_title：ACS chemical biology

authors： Garland M,Babin BM,Miyashita SI,Loscher S,Shen Y,Dong M,Bogyo M

更新日期：2019-01-18 00:00:00

abstract：:Regulators of G protein signaling (RGS) proteins are key players in regulating signaling via G protein-coupled receptors. RGS proteins directly bind to the Gα-subunits of activated heterotrimeric G-proteins, and accelerate the rate of GTP hydrolysis, thereby rapidly deactivating G-proteins. Using atomistic simulations...

journal_title：ACS chemical biology

authors： Vashisth H,Storaska AJ,Neubig RR,Brooks CL 3rd

更新日期：2013-12-20 00:00:00

abstract：:Ammonia lyases catalyze the formation of α,β-unsaturated bonds by the elimination of ammonia from their substrates. This conceptually straightforward reaction has been the emphasis of many studies, with the main focus on the catalytic mechanism of these enzymes and/or the use of these enzymes as catalysts for the synt...

journal_title：ACS chemical biology

authors： de Villiers M,Puthan Veetil V,Raj H,de Villiers J,Poelarends GJ

更新日期：2012-10-19 00:00:00