PPI inhibitor and stabilizer development in human diseases
Publication date: Available online 31 October 2017 Source:Drug Discovery Today: Technologies Author(s): Jürgen Bosch All processes in living organisms are regulated by, or at least influenced by, protein–protein interactions (PPI). Membrane proteins play a fundamental part in this class of interactions: by providing inter-cellular communication and sensing capabilities to the cell, they lead to downstream regulation signaling events. It is therefore not surprising that PPI modulators are of keen interest when developing drug-like molecules for a range of diseases and medical conditions. However, techniques for exploi...
Source: Drug Discovery Today: Technologies - November 10, 2017 Category: Drugs & Pharmacology Source Type: research
The Keap1 –Nrf2 protein–protein interaction: A suitable target for small molecules
Publication date: Available online 31 October 2017 Source:Drug Discovery Today: Technologies Author(s): Dieter Schmoll, Christian K. Engel, Heiner Glombik The transcription factor Nrf2 controls pathways involved in oxidative-stress defense and is a potential pharmacological target for the treatment of chronic diseases. Activators of Nrf2 that have undergone clinical development are reactive molecules that are either associated with safety issues or for which it is unclear if their pharmacological efficacy depends on the activation of Nrf2. Therefore, the clinical validity of Nrf2 activation is not yet proven. The acti...
Source: Drug Discovery Today: Technologies - November 10, 2017 Category: Drugs & Pharmacology Source Type: research
Imaging the glutamate receptor subtypes —Much achieved, and still much to do
Publication date: Available online 8 November 2017 Source:Drug Discovery Today: Technologies Author(s): Stefan Gruber, Simon M. Ametamey Functional imaging of glutamate receptors using PET imaging modality can be used to study numerous CNS disorders and also to select appropriate doses of clinically relevant glutamate-receptor-targeting candidate drugs. Great strides have been made in developing PET imaging probes for the non-invasive detection of glutamate receptors in the brain. This review highlights recent progress made towards the development of glutamatergic PET imaging agents. Focus is placed on PET imaging prob...
Source: Drug Discovery Today: Technologies - November 10, 2017 Category: Drugs & Pharmacology Source Type: research
Empirical drug discovery: a view from the proteome
Publication date: March 2017 Source:Drug Discovery Today: Technologies, Volume 23 Author(s): Jonathan A. Lee, Neil O. Carragher, Ellen L. Berg (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - June 22, 2017 Category: Drugs & Pharmacology Source Type: research
The evolution of library design: crafting smart compound collections for phenotypic screens
Publication date: Available online 30 May 2017 Source:Drug Discovery Today: Technologies Author(s): 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 ...
Source: Drug Discovery Today: Technologies - May 31, 2017 Category: Drugs & Pharmacology Source Type: research
Reverse Phase Protein Arrays elucidate mechanisms-of-action and phenotypic response in 2D and 3D models
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. (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - May 31, 2017 Category: Drugs & Pharmacology Source Type: research
In vivo phenotypic screening: clinical proof of concept for a drug repositioning approach
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. These findings validate an in vivo screening approach for drug development and underscore the importance of alternatives to target and mechanism based strategies that have failed to produce adequate numbers of new medicines. (...
Source: Drug Discovery Today: Technologies - May 17, 2017 Category: Drugs & Pharmacology Source Type: research
Targeting neuronal function for CNS drug discovery
Publication date: Available online 6 May 2017 Source:Drug Discovery Today: Technologies Author(s): 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 a...
Source: Drug Discovery Today: Technologies - May 6, 2017 Category: Drugs & Pharmacology Source Type: research
Phenotypic screening —the fast track to novel antibody discovery
Publication date: Available online 25 April 2017 Source:Drug Discovery Today: Technologies Author(s): 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 candida...
Source: Drug Discovery Today: Technologies - April 26, 2017 Category: Drugs & Pharmacology Source Type: research
The production of 3D tumor spheroids for cancer drug discovery
Publication date: Available online 14 April 2017 Source:Drug Discovery Today: Technologies Author(s): 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 accuratel...
Source: Drug Discovery Today: Technologies - April 15, 2017 Category: Drugs & Pharmacology Source Type: research
Natural product inspired compound collections: evolutionary principle, chemical synthesis, phenotypic screening, and target identification
Publication date: Available online 14 April 2017 Source:Drug Discovery Today: Technologies Author(s): 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 ...
Source: Drug Discovery Today: Technologies - April 14, 2017 Category: Drugs & Pharmacology Source Type: research
Phenotypic chemical biology for predicting safety and efficacy
Publication date: Available online 4 April 2017 Source:Drug Discovery Today: Technologies Author(s): 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...
Source: Drug Discovery Today: Technologies - April 4, 2017 Category: Drugs & Pharmacology Source Type: research
Bioprinted three dimensional human tissues for toxicology and disease modeling
Publication date: Available online 28 March 2017 Source:Drug Discovery Today: Technologies Author(s): 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 pr...
Source: Drug Discovery Today: Technologies - March 29, 2017 Category: Drugs & Pharmacology Source Type: research
Deorphanization strategies for dark chemical matter
Publication date: Available online 27 February 2017 Source:Drug Discovery Today: Technologies Author(s): 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 s...
Source: Drug Discovery Today: Technologies - February 27, 2017 Category: Drugs & Pharmacology Source Type: research
Exploiting transferrin receptor for delivering drugs across the blood-brain barrier
Publication date: June 2016 Source:Drug Discovery Today: Technologies, Volume 20 Author(s): Judy Paterson, Carl I. Webster Delivery of large molecule drugs across the blood brain barrier is increasingly being seen as an achievable goal. Several technologies have been described where following peripheral administration the molecules can be detected in the brain. Foremost amongst these technologies are antibodies against the transferrin receptor. Following a burst of publications in the very early twenty first century, excitement seemed to wane as contrary data started to emerge. Over the last few years antibodies agains...
Source: Drug Discovery Today: Technologies - December 13, 2016 Category: Drugs & Pharmacology Source Type: research
