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Drug Discovery Today. Technologies

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https://www.readbyqxmd.com/read/28647091/phenotypic-screening-the-fast-track-to-novel-antibody-discovery
#1
REVIEW
Ralph R Minter, Alan M Sandercock, Steven J Rust
The majority of antibody therapeutics have been isolated from target-led drug discovery, where many years of target research preceded drug program initiation. However, as the search for validated targets becomes more challenging and target space becomes increasingly competitive, alternative strategies, such as phenotypic drug discovery, are gaining favour. This review highlights successful examples of antibody phenotypic screens that have led to clinical drug candidates. We also review the requirements for performing an effective antibody phenotypic screen, including antibody enrichment and target identification strategies...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647090/natural-product-inspired-compound-collections-evolutionary-principle-chemical-synthesis-phenotypic-screening-and-target-identification
#2
REVIEW
Luca Laraia, Herbert Waldmann
Natural products have been an excellent and abundant source of therapeutics for many decades. To expand on their success, and explore areas of chemical space not covered by biosynthesis, the synthesis of natural product-inspired compound collections has emerged as a viable strategy. Herein we describe the principles behind biology-oriented synthesis and related approaches, the requirements for development of novel chemistry and how phenotypic screens are a very fruitful way to explore the bioactivity of compounds made using these approaches...
March 2017: Drug Discovery Today. Technologies
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/28647088/deorphanization-strategies-for-dark-chemical-matter
#4
REVIEW
Anne Mai Wassermann, Matthew Tudor, Meir Glick
The term dark chemical matter (DCM) was recently introduced for those molecules in a screening collection that have never shown any substantial biological activity despite having been tested in hundreds of high-throughput assays. It was suggested that, if hits emerge from this compound pool in future screening campaigns, they should be prioritized due to their exquisite selectivity profile. In this article we define DCM at our company and describe on-going efforts to shed light on the bioactivity of these apparently silent compounds, with an emphasis on multi-parametric profiling methods...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647087/the-evolution-of-library-design-crafting-smart-compound-collections-for-phenotypic-screens
#5
REVIEW
Kerry L Spear, Scott P Brown
The (re)emergence of phenotypic drug discovery has been marked by a growing interest in screening campaigns that utilize phenotypic assays. The key objectives of phenotypic screens are different from those of target-based screens and can require alternate library-design strategies. Designing a library that is appropriate to the selected assay increases the likelihood of identifying better quality hits, which can reduce both timelines and overall cost of the drug-discovery process. Here, we provide an overview of small-molecule library design principles as applied to phenotypic screening...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647086/phenotypic-chemical-biology-for-predicting-safety-and-efficacy
#6
REVIEW
Ellen L Berg
Phenotypic assays using in vitro cell cultures to forecast compound effects in people are transforming pharmaceutical research and contribute to alternative methods for chemical safety testing. How these assays are validated for human disease relevance is a critical factor for developing more predictive assays. Chemical biology, using drugs as well as target-selective chemical probes, is a direct and efficient approach for establishing disease relevance. Chemical probes can connect information across assays and associate targets to clinical effects...
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
#7
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/28647084/bioprinted-three-dimensional-human-tissues-for-toxicology-and-disease-modeling
#8
REVIEW
Deborah G Nguyen, Stephen L Pentoney
The high rate of attrition among clinical-stage therapies, due largely to an inability to predict human toxicity and/or efficacy, underscores the need for in vitro models that better recapitulate in vivo human biology. In much the same way that additive manufacturing has revolutionized the production of solid objects, three-dimensional (3D) bioprinting is enabling the automated production of more architecturally and functionally accurate in vitro tissue culture models. Here, we provide an overview of the most commonly used bioprinting approaches and how they are being used to generate complex in vitro tissues for use in toxicology and disease modeling research...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647083/the-production-of-3d-tumor-spheroids-for-cancer-drug-discovery
#9
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
#10
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/28647081/empirical-drug-discovery-a-view-from-the-proteome
#11
EDITORIAL
Jonathan A Lee, Neil O Carragher, Ellen L Berg
No abstract text is available yet for this article.
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978993/leverage-nonclinical-development-of-bispecifics-by-translational-science
#12
REVIEW
Andreas Baumann, Stephanie Fischmann, Guenter Blaich, Matthias Friedrich
Bispecific antibody constructs (Bispecifics, bsAbs) may have greater functionality compared to established monoclonal antibodies because they bind to 2 different targets or, potentially, to 2 epitopes on the same target (dual targeting). This may result in enhanced binding avidity with preferential binding to cells that express both targets or binding to targets on different cells. However, development of these next-generation biologics, including new formats, creates unique challenges due to their increased complexity...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978992/translational-immunotoxicology-of-immunomodulatory-monoclonal-antibodies
#13
REVIEW
Frank R Brennan, Andrea Kiessling
While immunomodulatory monoclonal antibodies (mAbs) have a wide therapeutic potential, exaggerated immunopharmacology may drive both acute and delayed immunotoxicity. The existing tools for immunotoxicity assessment do not accurately predict the full range of immunotoxicities observed in humans. New and optimized models, assays, endpoints and biomarkers in animals and humans are required to safeguard patients and allow them access to these often transformational therapies.
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978991/translational-pharmacokinetics-and-pharmacodynamics-of-monoclonal-antibodies
#14
REVIEW
Amrita V Kamath
Monoclonal antibodies (mAbs) are an important therapeutic class with complex pharmacology and interdependent pharmacokinetic (PK) and pharmacodynamics (PD) properties. Understanding the PK and PD of mAbs and their biological and mechanistic underpinnings are crucial in enabling their design and selection, designing appropriate efficacy and toxicity studies, translating PK/PD parameters to humans, and optimizing dose and regimen to maximize success in the clinic. Significant progress has been made in this field however many critical questions still remain...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978990/perspectives-in-regulatory-science-translational-and-clinical-pharmacology
#15
REVIEW
Joseph A Grillo, Shiew Mei Huang
This paper focuses on the role of clinical and translational pharmacology in the drug development and the regulatory process. Contemporary regulatory issues faced by FDA's Office of Clinical Pharmacology (OCP) in fulfilling its mission to advance the science of drug response and translate patient diversity into optimal drug therapy are discussed. Specifically current focus of the following key aspects of the drug development and regulatory science processes are discussed: the OCP vision and mission, two key OCP initiatives (i...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978989/quantitative-systems-pharmacology-a-promising-approach-for-translational-pharmacology
#16
REVIEW
K Gadkar, D Kirouac, N Parrott, S Ramanujan
Biopharmaceutical companies have increasingly been exploring Quantitative Systems Pharmacology (QSP) as a potential avenue to address current challenges in drug development. In this paper, we discuss the application of QSP modeling approaches to address challenges in the translational of preclinical findings to the clinic, a high risk area of drug development. Three cases have been highlighted with QSP models utilized to inform different questions in translational pharmacology. In the first, a mechanism based asthma model is used to evaluate efficacy and inform biomarker strategy for a novel bispecific antibody...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978988/translational-pharmacokinetic-pharmacodynamic-analysis-in-cancer-pharmacology-a-tool-to-maximize-the-value-of-antitumor-efficacy-from-tumor-bearing-mice
#17
REVIEW
Harvey Wong, Stephen E Gould
Translational pharmacokinetic/pharmacodynamic (PK/PD) analysis is becoming an increasingly important tool for the identification and selection of new anticancer agents. There are two important elements of effectively using PK/PD analysis to translate preclinical antitumor efficacy from tumor bearing mice (xenografts and allografts) to cancer patients. These two sometimes overlapping elements are termed translation 'WITHIN' and 'ACROSS' species. Translating 'WITHIN' species refers to the quantitative characterization of drug action and disease behavior within tumor bearing mice using PK/PD modeling in order to use this information to make predictions of drug response in humans...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978987/translational-pk-pd-of-anti-infective-therapeutics
#18
REVIEW
Chetan Rathi, Richard E Lee, Bernd Meibohm
Translational PK/PD modeling has emerged as a critical technique for quantitative analysis of the relationship between dose, exposure and response of antibiotics. By combining model components for pharmacokinetics, bacterial growth kinetics and concentration-dependent drug effects, these models are able to quantitatively capture and simulate the complex interplay between antibiotic, bacterium and host organism. Fine-tuning of these basic model structures allows to further account for complicating factors such as resistance development, combination therapy, or host responses...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978986/pharmacological-considerations-for-predicting-pk-pd-at-the-site-of-action-for-therapeutic-proteins
#19
REVIEW
Weirong Wang, Honghui Zhou
For therapeutic proteins whose sites of action are distal to the systemic circulation, both drug and target concentrations at the tissue sites are not necessarily proportional to those in systemic circulation, highlighting the importance of understanding pharmacokinetic/pharmacodynamic (PK/PD) relationship at the sites of action. This review summarizes the pharmacological considerations for predicting local PK/PD and the importance of measuring PK and PD at site of action. Three case examples are presented to show how mechanistic and physiologically based PK/PD (PBPK/PD) models which incorporated the PK and PD at the tissue site can be used to facilitate understanding the exposure-response relationship for therapeutic proteins...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978985/translational-biomarkers-from-discovery-and-development-to-clinical-practice
#20
REVIEW
Meena Subramanyam, Jaya Goyal
The refinement of disease taxonomy utilizing molecular phenotypes has led to significant improvements in the precision of disease diagnosis and customization of treatment options. This has also spurred efforts to identify novel biomarkers to understand the impact of therapeutically altering the underlying molecular network on disease course, and to support decision-making in drug discovery and development. However, gaps in knowledge regarding disease heterogeneity, combined with the inadequacies of surrogate disease model systems, make it challenging to demonstrate the unequivocal association of molecular and physiological biomarkers to disease pathology...
September 2016: Drug Discovery Today. Technologies
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