The exploitation of FRET probes to track bromodomain/histone interactions in cells for bromodomain inhibitors
Publication date: Available online 20 July 2016 Source:Drug Discovery Today: Technologies Author(s): Kazuki Sasaki, Minoru Yoshida Bromodomain-containing proteins are epigenetic readers of histone codes, which recognize acetylated histones and are involved in transcription, nucleosome remodeling and DNA repair. Chromosomal translocations of bromodomain-containing proteins have been implicated in many diseases. In this regard, small molecules that inhibit bromodomains are promising as therapeutic agents. A fluorescence microscopy-based approach provides information on bromodomain inhibitors that abrogate the interac...
Source: Drug Discovery Today: Technologies - July 21, 2016 Category: Drugs & Pharmacology Source Type: research
Development of small molecule inhibitors of BRPF1 and TRIM24 bromodomains
Publication date: Available online 21 July 2016 Source:Drug Discovery Today: Technologies Author(s): Wylie S. Palmer The entry of small molecule inhibitors of the bromodomain and extra C-terminal domain (BET) family of bromodomains into the clinic has demonstrated the therapeutic potential for this class of epigenetic acetyl-lysine reader proteins. Within the past two years, the development of potent inhibitors for the bromodomain and PHD finger containing protein (BRPF) family and the tripartite motif containing protein 24 (TRIM24) have been reported and are the subject of this review. Both proteins contain other do...
Source: Drug Discovery Today: Technologies - July 21, 2016 Category: Drugs & Pharmacology Source Type: research
Clinical trials for BET inhibitors run ahead of the science
Publication date: Available online 21 July 2016 Source:Drug Discovery Today: Technologies Author(s): Guillaume Andrieu, Anna C. Belkina, Gerald V. Denis Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partia...
Source: Drug Discovery Today: Technologies - July 21, 2016 Category: Drugs & Pharmacology Source Type: research
Fragment-based in silico screening of bromodomain ligands
Publication date: Available online 21 July 2016 Source:Drug Discovery Today: Technologies Author(s): Dimitrios Spiliotopoulos, Amedeo Caflisch We review the results of fragment-based high-throughput docking to the N-terminal bromodomain of BRD4 and the CREBBP bromodomain. In both docking campaigns the ALTA (anchor-based library tailoring) procedure was used to reduce the size of the initial library by selecting for flexible docking only the molecules that contain a fragment with favorable predicted binding energy. Ranking by a force field-based energy with solvation has resulted in small-molecule hits with low-micr...
Source: Drug Discovery Today: Technologies - July 21, 2016 Category: Drugs & Pharmacology Source Type: research
Kinetic analysis of drug –protein interactions by affinity chromatography
Publication date: October 2015 Source:Drug Discovery Today: Technologies, Volume 17 Author(s): Cong Bi, Sandya Beeram, Zhao Li, Xiwei Zheng, David S. Hage Information on the kinetics of drug–protein interactions is of crucial importance in drug discovery and development. Several methods based on affinity chromatography have been developed in recent years to examine the association and dissociation rates of these processes. These techniques include band-broadening measurements, the peak decay method, peak fitting methods, the split-peak method, and free fraction analysis. This review will examine the general...
Source: Drug Discovery Today: Technologies - July 20, 2016 Category: Drugs & Pharmacology Source Type: research
On-rate based optimization of structure –kinetic relationship – surfing the kinetic map
This article reviews various approaches to monitor SKR and suggests using the on-rate as the key monitoring parameter. The literature is reviewed and examples of compound series with low variability as well as with significant changes in on-rates are highlighted. Furthermore, findings of kinetic on-rate changes are presented and potential underlying rationales are discussed. (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - July 20, 2016 Category: Drugs & Pharmacology Source Type: research
Kinetic binding assays for the analysis of protein –ligand interactions
Publication date: October 2015 Source:Drug Discovery Today: Technologies, Volume 17 Author(s): Franz-Josef Meyer-Almes The importance of binding kinetics in terms of residence time and on-rate in drug discovery has been broadly accepted in the past few years. Furthermore, evidence has accumulated that the optimal binding mechanism of a drug to its target molecule is related to physiological efficacy as well as selectivity and thus drug safety. Homogeneous fluorescence-based binding assays have been shown to enable high throughput kinetics requiring only small amounts of protein and can be developed to elucidate even ...
Source: Drug Discovery Today: Technologies - July 20, 2016 Category: Drugs & Pharmacology Source Type: research
Phospho-BRD4: transcription plasticity and drug targeting
Publication date: Available online 18 July 2016 Source:Drug Discovery Today: Technologies Author(s): Cheng-Ming Chiang BRD4 is an epigenetic regulator and transcription cofactor whose phosphorylation by CK2 and dephosphorylation by PP2A modulates its function in chromatin targeting, factor recruitment, and cancer progression. While the bromodomains of BET family proteins, including BRD4, BRD2, BRD3 and BRDT, have been the primary targets of small compounds such as JQ1, I-BET and MS417 that show promising anticancer effects against some hematopoietic cancer and solid tumors, drug resistance upon prolonged treatment ne...
Source: Drug Discovery Today: Technologies - July 18, 2016 Category: Drugs & Pharmacology Source Type: research
Binding kinetics in drug discovery
Publication date: October 2015 Source:Drug Discovery Today: Technologies, Volume 17 Author(s): Xavier Barril, Helena Danielsson (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - December 12, 2015 Category: Drugs & Pharmacology Source Type: research
Challenges in profiling and lead optimization of drug discovery for methyltransferases
Publication date: November 2015 Source:Drug Discovery Today: Technologies, Volume 18 Author(s): Kurumi Y. Horiuchi The importance of epigenetics in the initiation and progression of disease has attracted many investigators to incorporate this novel and exciting field in drug development. Protein methyltransferases are one of the target classes which have gained attention as potential therapeutic targets after promising results of inhibitors for EZH2 and DOT1L in clinical trials. There are many technologies developed in order to find small molecule inhibitors for protein methyltransferases. However, in contrast to hig...
Source: Drug Discovery Today: Technologies - November 23, 2015 Category: Drugs & Pharmacology Source Type: research
Kinase profiling in early stage drug discovery: sorting things out
Publication date: November 2015 Source:Drug Discovery Today: Technologies, Volume 18 Author(s): Olivier Defert, Sandro Boland Protein kinases represent one of the largest superfamilies of drugable targets and a major research area for both the pharmaceutical industry and academic groups. This has resulted in the emergence of numerous screening technologies and services dedicated to kinase profiling. In spite of this plentiful offering, the field is not without its own pitfalls, as the profusion of reported conditions and data can ultimately complicate interpretation of project results. Here, we discuss how kinase p...
Source: Drug Discovery Today: Technologies - November 18, 2015 Category: Drugs & Pharmacology Source Type: research
Screening and profiling assays for HDACs and sirtuins
Publication date: November 2015 Source:Drug Discovery Today: Technologies, Volume 18 Author(s): Konrad T. Howitz Epigenetic factors are enzymes or proteins that confer, remove or recognize covalent modifications to chromatin DNA or proteins. They can be divided into three broad groups, commonly referred to as the ‘writers’, ‘erasers’ and ‘readers’. The HDACs and sirtuins, which remove acetyl groups from the ɛ-amino of protein lysine residues, fall into the ‘eraser’ category. Due to their important effects on gene expression and involvement in various disease states, these enzymes have been the subjec...
Source: Drug Discovery Today: Technologies - November 8, 2015 Category: Drugs & Pharmacology Source Type: research
GPCR profiling: from hits to leads and from genotype to phenotype
This article focuses on GPCR platform strategies from hits to leads with miniaturized complex pharmacology approaches. Three main areas of GPCR profiling are discussed including pharmacologically relevant hit identification, the pharmacology dossier applied to parallel structure activity and structure liability relationships and high-throughput mechanism studies from genotype to phenotype. (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - November 8, 2015 Category: Drugs & Pharmacology Source Type: research
Technologies to develop new metal medicines
Publication date: September 2015 Source:Drug Discovery Today: Technologies, Volume 16 Author(s): Francois Dufrasne (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - November 5, 2015 Category: Drugs & Pharmacology Source Type: research
Profiling technologies for the identification and characterization of small-molecule histone deacetylase inhibitors
Publication date: November 2015 Source:Drug Discovery Today: Technologies, Volume 18 Author(s): Daiqing Liao Histone deacetylases (HDACs) are promising drug targets for treating cancer, neurologic, inflammatory and metabolic diseases. Four small molecule inhibitors of HDACs have gained regulatory approval for treating lymphomas and multiple myelomas. Highly sensitive in vitro and cell-based profiling technologies have been developed to discover HDAC inhibitors (HDACi) and characterize their inhibitory potency, target-binding specificity and kinetics. In particular, proteomic profiling can define the specificity of an...
Source: Drug Discovery Today: Technologies - November 5, 2015 Category: Drugs & Pharmacology Source Type: research
