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https://www.readbyqxmd.com/read/28647489/a-high-throughput-assay-to-identify-substrate-selective-inhibitors-of-the-erk-protein-kinases
#1
Chad J Miller, Yagmur Muftuoglu, Benjamin E Turk
Extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylate a variety of substrates important for survival and proliferation, and their activity is frequently deregulated in tumors. ERK pathway inhibitors have shown clinical efficacy as anti-cancer drugs, but most patients eventually relapse due to reactivation of the pathway. One factor limiting the efficacy of current therapeutics is the difficulty in reaching clinically effective inhibition of the ERK pathway in the absence of on-target toxicities...
June 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28647378/leishmaniasis-drug-discovery-recent-progress-and-challenges-in-assay-development
#2
REVIEW
Bilal Zulfiqar, Todd B Shelper, Vicky M Avery
Leishmaniasis, caused by the trypanosomatid protozoan Leishmania, is endemic in 98 countries worldwide, with morbidity and mortality increasing daily. Despite available drugs, leishmaniasis faces the challenge of emerging resistance and toxicity concerns for current drug regimes. Identification of anti-leishmanial compounds representing new chemistry and novel mechanisms of action is essential to populate the drug discovery pipeline. The in vitro assays currently available have shown poor translational outcomes, with high compound attrition rates...
June 21, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28647089/reverse-phase-protein-arrays-elucidate-mechanisms-of-action-and-phenotypic-response-in-2d-and-3d-models
#3
REVIEW
Michael Pawlak, Neil O Carragher
The development of new 2D and 3D phenotypic screening assays combined with high-throughput genomic and proteomic technologies are well placed to advance a new era of molecular pathway informed Phenotypic Drug Discovery. We describe the application of Reverse Phase Protein Array (RPPA) technology to elucidate the mechanism-of-action of small molecules at the post-translational pathway level. We propose that profiling of phenotypic hits and lead molecules in increasingly more complex 3D in vitro and ex vivo models at the post-translational pathway network level represents an effective strategy to both triage and progress the preclinical development of phenotypic screening hits...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647085/in-vivo-phenotypic-screening-clinical-proof-of-concept-for-a-drug-repositioning-approach
#4
REVIEW
John R Ciallella, Andrew G Reaume
In vivo phenotypic screening and drug repositioning are strategies developed as alternatives to underperforming hypothesis-driven molecular target based drug discovery efforts. This article reviews examples of drugs identified by phenotypic observations and describes the use of the theraTRACE(®)in vivo screening platform for finding and developing new indications for discontinued clinical compounds. Clinical proof-of-concept for the platform is exemplified by MLR-1023, a repositioned compound that has recently shown significant clinical efficacy in Type 2 diabetes patients...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647083/the-production-of-3d-tumor-spheroids-for-cancer-drug-discovery
#5
REVIEW
Shilpa Sant, Paul A Johnston
New cancer drug approval rates are ≤5% despite significant investments in cancer research, drug discovery and development. One strategy to improve the rate of success of new cancer drugs transitioning into the clinic would be to more closely align the cellular models used in the early lead discovery with pre-clinical animal models and patient tumors. For solid tumors, this would mandate the development and implementation of three dimensional (3D) in vitro tumor models that more accurately recapitulate human solid tumor architecture and biology...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647082/targeting-neuronal-function-for-cns-drug-discovery
#6
REVIEW
Chris M Hempel, Christopher A Werley, Graham T Dempsey, David J Gerber
There is a pressing need for new and more effective treatments for central nervous system (CNS) disorders. A large body of evidence now suggests that alterations in synaptic transmission and neuronal excitability represent underlying factors for many neurological and psychiatric diseases. However, it has been challenging to target these complex functional domains for therapeutic discovery using traditional neuronal assay methods. Here we review advances in neuronal screening technologies and cellular model systems that enable phenotypic screening of neuronal function as a basis for novel CNS drug discovery approaches...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28645238/new-world-arenavirus-biology
#7
Nicolás Sarute, Susan R Ross
Hemorrhagic fevers caused by viruses were identified in the late 1950s in South America. These viruses have existed in their hosts, the New World rodents, for millions of years. Their emergence as infectious agents in humans coincided with changes in the environment and farming practices that caused explosions in their host rodent populations. Zoonosis into humans likely occurs because the pathogenic New World arenaviruses use human transferrin receptor 1 to enter cells. The mortality rate after infection with these viruses is high, but the mechanism by which disease is induced is still not clear...
June 23, 2017: Annual Review of Virology
https://www.readbyqxmd.com/read/28644739/treatment-of-hepatitis-c-with-new-fixed-dose-combinations
#8
Vicente Soriano
The advent of oral direct-acting antivirals (DAA) has revolutionized the hepatitis C virus (HCV) therapeutic landscape providing cure rates over 90%. However, a subset of patients remains at higher risk for treatment failure, including those infected with: i) genotype 3 and cirrhosis; ii) resistance-associated substitutions (RAS) occurring either as natural polymorphisms or selected after prior DAA failure; and iii) poor drug adherence associated with social disabilities (homeless, psychiatric illnesses, injection drug use, alcoholism, etc...
June 23, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28644461/a-new-school-of-drug-discovery
#9
Ellen P Neff
No abstract text is available yet for this article.
June 23, 2017: Lab Animal
https://www.readbyqxmd.com/read/28643372/fine-tuning-perk-signaling-for-neuroprotection
#10
REVIEW
Mark Halliday, Daniel Hughes, Giovanna Mallucci
Protein translation and folding are tightly controlled processes in all cells, by proteostasis, an important component of which is the unfolded protein response (UPR). During periods of endoplasmic reticulum stress due to protein misfolding, the UPR activates a coordinated response in which the PERK branch activation restricts translation, while a variety of genes involved with protein folding, degradation, chaperone expression and stress responses are induced through signaling of the other branches. Chronic overactivation of the UPR, particularly the PERK branch is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the taopathies...
June 23, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28640968/the-impact-of-andean-patagonian-mycoflora-in-the-search-for-new-lead-molecules
#11
REVIEW
Pedro M Aqueveque, Carlos L Cespedes, Isao Kubo, David S Seigler, Olov Sterner
Secondary metabolites from fungi have become a major source of chemical innovation in programs searching for lead molecules with bioactivities, especially over the last 50 years. In this review, we discuss the fundamental considerations in the discovery of molecules for agricultural and medicinal uses. This group of organisms possesses a strong potential for scientific and industrial communities. Recently, the incorporation of new technologies for the artificial cultivation of fungi and the use of better equipment to isolate and identify active metabolites has allowed the discovery of leading molecules for the design of new and safer drugs and pesticides...
June 22, 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/28638861/randomized-anticancer-and-cytotoxicity-activities-of-guibourtia-coleosperma-and-diospyros-chamaethamnus
#12
Florence Dushimemaria, C Iwanette Du Preez, Davis R Mumbengegwi
BACKGROUND: Plants have consistently proven to be a reliable and yet not fully explored source of medicines. In light of this, there is a constant demand for new treatment regimens for cancer. Namibia has a rich diversity of plant species of over 4300 with 17 % of them being endemic to Namibia. Plants growing in Namibia's diverse climatic zones produce many secondary metabolites as part of adaptation to their environment. This article focused on the screening of such phytochemicals and their cytotoxic and anticancer properties in vitro...
2017: African Journal of Traditional, Complementary, and Alternative Medicines: AJTCAM
https://www.readbyqxmd.com/read/28638591/replicable-in-vivo-physiological-and-behavioral-phenotypes-of-the-shank3b-null-mutant-mouse-model-of-autism
#13
Sameer C Dhamne, Jill L Silverman, Chloe E Super, Stephen H T Lammers, Mustafa Q Hameed, Meera E Modi, Nycole A Copping, Michael C Pride, Daniel G Smith, Alexander Rotenberg, Jacqueline N Crawley, Mustafa Sahin
BACKGROUND: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD...
2017: Molecular Autism
https://www.readbyqxmd.com/read/28638489/harnessing-integrative-omics-to-facilitate-molecular-imaging-of-the-human-epidermal-growth-factor-receptor-family-for-precision-medicine
#14
REVIEW
Martin Pool, H Rudolf de Boer, Marjolijn N Lub-de Hooge, Marcel A T M van Vugt, Elisabeth G E de Vries
Cancer is a growing problem worldwide. The cause of death in cancer patients is often due to treatment-resistant metastatic disease. Many molecularly targeted anticancer drugs have been developed against 'oncogenic driver' pathways. However, these treatments are usually only effective in properly selected patients. Resistance to molecularly targeted drugs through selective pressure on acquired mutations or molecular rewiring can hinder their effectiveness. This review summarizes how molecular imaging techniques can potentially facilitate the optimal implementation of targeted agents...
2017: Theranostics
https://www.readbyqxmd.com/read/28637488/a-high-throughput-colorimetric-assay-for-detection-of-schistosoma-mansoni-viability-based-on-the-tetrazolium-salt-xtt
#15
Pedro Henrique Nascimento Aguiar, Núbia Monteiro Gonçalves Soares Fernandes, Carlos Leomar Zani, Marina Moraes Mourão
BACKGROUND: Schistosoma mansoni is a trematode parasite that causes schistosomiasis, one of the most prevalent neglected tropical diseases, leading to the loss of 2.6 million disability-adjusted life years. Praziquantel is the only drug available, and new drugs are required. The most common strategy in schistosomiasis drug discovery is the use of the schistosomula larval-stage for a pre-screen in drug sensitivity assays. However, assessing schistosomula viability by microscopy has always been a limitation to the throughput of such assays...
June 21, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28637123/inhibition-of-swarming-motility-of-pseudomonas-aeruginosa-by-methanol-extracts-of-alpinia-officinarum-hance-and-cinnamomum-tamala-t-nees-and-eberm
#16
Divya Lakshmanan, Jishudas Nanda, K Jeevaratnam
Bacterial drug resistance is a challenge in clinical settings, especially in countries like India. Hence, discovery of novel alternative therapeutics has become a necessity in the fight against drug resistance. Compounds that inhibit bacterial virulence properties form new therapeutic alternatives. Pseudomonas aeruginosa is an opportunistic, nosocomial pathogen that infects immune-compromised patients. Swarming motility is an important virulence property of Pseudomonas which aids it in reaching host cells under nutrient limiting conditions...
June 15, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28637000/precision-medicine-for-hepatocellular-carcinoma-driver-mutations-and-targeted-therapy
#17
REVIEW
Xiao-Xiao Ding, Qing-Ge Zhu, Shi-Ming Zhang, Lei Guan, Ting Li, Lei Zhang, Shi-Yang Wang, Wan-Li Ren, Xue-Mei Chen, Jing Zhao, Song Lin, Zhi-Zhen Liu, Yan-Xia Bai, Bing He, Hu-Qin Zhang
Hepatocellular carcinoma (HCC) is the third most frequent cause of tumor-related mortality and there are an estimated approximately 850,000 new cases annually. Most HCC patients are diagnosed at middle or advanced stage, losing the opportunity of surgery. The development of HCC is promoted by accumulated diverse genetic mutations, which confer selective growth advantages to tumor cells and are called "driver mutations". The discovery of driver mutations provides a novel precision medicine strategy for late stage HCC, called targeted therapy...
June 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636912/channeling-of-camp-in-pde-pka-complexes-promotes-signal-adaptation
#18
Nikhil Kumar Tulsian, Srinath Krishnamurthy, Ganesh Srinivasan Anand
Spatiotemporal control of the cAMP signaling pathway is governed by both hormonal stimulation of cAMP generation by adenylyl cyclases (activation phase) and cAMP hydrolysis by phosphodiesterases (PDEs) (termination phase). The termination phase is initiated by PDEs actively targeting the protein kinase A (PKA) R-subunit through formation of a PDE-PKAR-cyclic adenosine monophosphate (cAMP) complex (the termination complex). Our results using PDE8 as a model PDE, reveal that PDEs mediate active hydrolysis of cAMP bound to its receptor RIα by enhancing the enzymatic activity...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28636311/insights-into-integrated-lead-generation-and-target-identification-in-malaria-and-tuberculosis-drug-discovery
#19
John Okombo, Kelly Chibale
New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public-private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery...
June 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28636189/discovery-of-alkyl-bis-oxy-dibenzimidamide-derivatives-as-novel-protein-arginine-methyltransferase-1-prmt1-inhibitors
#20
Wei-Yao Zhang, Wen-Chao Lu, Hao Jiang, Zheng-Bing Lv, Yi-Qian Xie, Fu-Lin Lian, Zhong-Jie Liang, Yu-Xi Jiang, Da-Jin Wang, Cheng Luo, Jia Jin, Fei Ye
Protein arginine methylation, a post-translational modification critical for a variety of biological processes, is catalyzed by protein arginine N-methyltransferases (PRMTs). In particular, PRMT1 is responsible for over 85% of the arginine methylation in mammalian cells. Dysregulation of PRMT1 is involved in diverse pathological diseases including cancers. However, most current PRMT1inhibitors are lack of specificity, efficacy, and bioavailability. Herein, a series of alkyl bis(oxy)dibenzimidamide derivatives were identified as selective PRMT1 inhibitors...
June 21, 2017: Chemical Biology & Drug Design
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