As demonstrated in multiple historical analyses, there are two main causes of clinical attrition; firstly drugs are not efficacious, and secondly they cause unacceptable toxicity, both of which can be the result of poor pre-clinical target validation. Target validation, one of the early stages of a drug discovery program, is the process of (in) validating a drug target to ensure it is significant to the intended disease, and unlikely to drive undesired toxicity. Target validation is vital in preventing late stage failures in the clinic and, if done effectively, can save pharmaceutical companies a great deal of time and money. As such, target validation is treated extremely seriously, as demonstrated by the formation of public - private partnerships, such as Open Targets, aimed to provide evidence of biological validity and the possible likelihood of pharmacological intervention. Central to the variety of molecular tools available for use in target validation are high quality small molecules called chemical probes.
The world today is increasingly confronted with systemic threats and challenges, in which femtorisks - small-scale dangers that are inherent to system structures and function and which pose asymmetrically catastrophic risks - can build in consequence, spreading uncontrollably like epidemics in both natural and social systems in such diverse areas as ecology, epidemiology, finance, the Internet, terrorism, and international relations. They have been successfully modeled in ecology in the context of complex adaptive systems: systems made up of individual agents, whose interactions have macroscopic consequences that feed back to influence individual behavior. While acknowledging challenges, this paper argues for the value of applying to societal systems the approaches that natural scientists have developed in quantifying and modeling biological interactions and ecosystems.
Non-BET bromodomain-containing proteins have become attractive targets for the development of novel therapeutics targeting epigenetic pathways. To help facilitate the target validation of this class of proteins, structurally diverse small-molecule ligands and methodologies to produce selective inhibitors in a predictable fashion are in high demand. Herein, we report the development and application of atypical acetyl-lysine (KAc) methyl mimetics to take advantage of the differential stability of conserved water molecules in the bromodomain binding site. Discovery of the n-butyl group as an atypical KAc methyl mimetic allowed generation of 31 (GSK6776) as a soluble, permeable, and selective BRD7/9 inhibitor from a pyridazinone template. The n-butyl group was then used to enhance the bromodomain selectivity of an existing BRD9 inhibitor and to transform pan-bromodomain inhibitors into BRD7/9 selective compounds. Finally, a solvent-exposed vector was defined from the pyridazinone template to enable bifunctional molecule synthesis, and affinity enrichment chemoproteomic experiments were used to confirm several of the endogenous protein partners of BRD7 and BRD9, which form part of the chromatin remodeling PBAF and BAF complexes, respectively.
Bromodomain containing proteins and the acetyl-lysine binding bromodomains contained therein are increasingly attractive targets for the development of novel epigenetic therapeutics. To help validate this target class and unravel the complex associated biology, there has been a concerted effort to develop selective small molecule bromodomain inhibitors. Herein we describe the structure-based efforts and multiple challenges encountered in optimizing a naphthyridone template into selective TAF1(2) bromodomain inhibitors which, while unsuitable as chemical probes themselves, show promise for the future development of small molecules to interrogate TAF1(2) biology. Key to this work was the introduction and modulation of the basicity of a pendant amine which had a substantial impact on not only bromodomain selectivity but also cellular target engagement.
The bromodomain and extra terminal (BET) family of bromodomain-containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high-quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non-BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non-BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non-BET bromodomains as tractable therapeutic targets.
The Cover Feature shows a CREBBP bromodomain surface as a representative non-BET bromodomain together with high-quality bromodomain probe molecules GNE-781, GSK4027, and GSK8814, which exemplify the advancements made in the development of non-BET bromodomain chemical probes since December 2015. The quality of non-BET bromodomain chemical probes, the accompanying supportive data, and the variety of chemotypes included have advanced dramatically in recent years, enabling robust target validation and is reflected in the important milestone of the first non-BET bromodomain inhibitor reaching human clinical trials. More information can be found in the Review by Philip G. Humphreys et al. on page 362 in Issue 4, 2019 (DOI: 10.1002/cmdc.201800738).
This report describes a method to fabricate high-surface-area boron-doped diamond (BDD) electrodes using so-called 'black silicon' (bSi) as a substrate. This is a synthetic nanostructured material that contains high-aspect-ratio nano-protrusions, such as spikes or needles, on the Si surface produced via plasma etching. We now show that coating a bSi surface composed of 15 μm-high needles conformably with BDD produces a robust electrochemical electrode with high sensitivity and high electroactive area. A clinically relevant demonstration of the efficacy of these electrodes is shown by measuring their sensitivity for detection of dopamine (DA) in the presence of an excess of uric acid (UA). Finally, the nanostructured surface of bSi has recently been found to generate a mechanical bactericidal effect, killing both Gram-negative and Gram-positive bacteria at high rates. We will show that BDD-coated bSi also acts as an effective antibacterial surface, with the added advantage that being diamond-coated it is far more robust and less likely to become damaged than Si.
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