Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology

Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains, the readers of acetyl-lysine modifications. A plethora of co-crystal structures has motivated focused fragment-based design and optimization programs within both industry and academia. These efforts have yielded several compounds entering the clinic, and many more are increasingly being used as chemical probes to interrogate bromodomain biology. High selectivity of chemical probes is necessary to ensure biological activity is due to an on-target effect. Here, we review the state-of-the-art of bromodomain-targeting compounds, focusing on the structural basis for their on-target selectivity or lack thereof. We also highlight chemical biology approaches to enhance on-target selectivity

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

Parametric investigation of flow-sound interaction mechanism of circular cylinders in cross-flow

Flow-excited acoustic resonance in heat exchangers has been an ongoing issue for the past century. The main challenge in this issue, is in the actual prediction of the resonance occurrence. This is due to the complexity of the flow-sound interaction mechanism that takes place between the packed cylinders. Most of the research lately has therefore shifted focus to simpler geometries that resemble the same mechanisms of flow-sound interaction found in actual heat-exchangers. The research presented hereafter summarizes an extensive experimental parametric work performed on multiple simple configurations such as single, tandem and side-by-side cylinders in cross-flow. The main objective of the research is to identify the critical parameters that should be included in the damping criteria to reliably predict the occurrence of acoustic resonance in tube bundles. Special attention is given to the geometrical characteristics of the duct (i.e. cross-sectional area) and how they affect the acoustic resonance. To achieve this; more than one hundred experiments have been performed in three different wind-tunnels of different cross-sectional areas. The research is motivated by the fact that most of the criteria developed to date, fail to predict the destructive phenomena of acoustic resonance in 30-40% of the cases

Expanding the Toolbox of E3 Ligases for Protein Degradation: Targeting the “Undruggable” Fbw7 E3 Ligase

Proteolysis targeting chimera molecules (PROTACS) are heterobifunctional small moleculesdesigned to induce intracellular protein degradation [...

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy

© 2020 by the authors.Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties. Preventing EET degradation thus increases its concentration in the brain through sEH inhibition, which represents a novel pharmacological approach to foster the reduction of neuroinflammation and by end neurodegeneration. Recently, it has been shown that sEH levels increase in brains of PD patients. Moreover, the pharmacological inhibition of the hydrolase domain of the enzyme or the use of sEH knockout mice reduced the deleterious effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. This paper overviews the knowledge of sEH and EETs in PD and the importance of blocking its hydrolytic activity, degrading EETs in PD physiopathology. We focus on imperative neuroinflammation participation in the neurodegenerative process in PD and the putative therapeutic role for sEH inhibitors. In this review, we also describe highlights in the general knowledge of the role of sEH in the central nervous system (CNS) and its participation in neurodegeneration. We conclude that sEH is one of the most promising therapeutic strategies for PD and other neurodegenerative diseases with chronic inflammation process, providing new insights into the crucial role of sEH in PD pathophysiology as well as a singular opportunity for drug developmentThis study was supported by the Ministerio de Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI) and Fondo Europeo de Desarrollo Regional (MINECO-FEDER) (Projects SAF2017-82771-R, SAF2016-33307, RTI2018-096429-B-100). C.G.-F., S.V., C.S., and M.P. belong to 2017SGR106 (Generalitat de Catalunya).Peer reviewe

Drugging the Fbw7 E3 Ligase with a Fragment-Based Approach

Fbw7 is an important E3 ligase and one of the most commonly deregulated proteins in human cancers. [...

Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein−Protein Interactions?

Modulation of protein−protein interactions (PPIs) with small molecules has been hampered by a lack of lucid methods capable of reliably identifying high-quality hits. In fragment screening, the low ligand efficiencies associated with PPI target sites pose significant challenges to fragment binding detection. Here, we investigate the requirements for ligand-based NMR techniques to detect rule-of-three compliant fragments that form part of known high-affinity inhibitors of the PPI between the von Hippel−Lindau protein and the alpha subunit of hypoxia-inducible factor 1 (pVHL:HIF-1α). Careful triaging allowed rescuing weak but specific binding of fragments that would otherwise escape detection at this PPI. Further structural information provided by saturation transfer difference (STD) group epitope mapping, protein-based NMR, competitive isothermal titration calorimetry (ITC), and X-ray crystallography confirmed the binding mode of the rescued fragments. Our findings have important implications for PPI druggability assessment by fragment screening as they reveal an accessible threshold for fragment detection and validation.This work was supported by the Fundação para a Ciência e a Tecnologia (FCT, SFRH/BD/81735/2011 Studentship to D.M.D.), the U.K. BBSRC (BB/G023123/1, David Phillips Fellowship to A.C.), the European Research Council ERC-2012- StG-311460 DrugE3CRLs (Starting Grant to A.C.), the EC PIEF-GA-2010-275683 (Marie-Curie Intra European Fellowship to I.V.M.), and the EMBO ASTF 165-2012 (Short-Term Fellowship to C.G.)