22 research outputs found
Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions
Focal adhesion tyrosine
kinase (PTK2) is often overexpressed in human hepatocellular carcinoma
(HCC), and several reports have linked PTK2 depletion and/or pharmacological
inhibition to reduced tumorigenicity. However, the clinical relevance
of targeting PTK2 still remains to be proven. Here, we present two
highly selective and functional PTK2 proteolysis-targeting chimeras
utilizing von Hippel–Lindau and cereblon ligands to hijack
E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades
PTK2 with a median DC<sub>50</sub> of 30 nM to >80% across a panel
of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds
did not phenocopy the reported antiproliferative effects of PTK2 depletion
in any of the cell lines tested. By disclosing these compounds, we
hope to provide valuable tools for the study of PTK2 degradation across
different biological systems
Direct NMR Probing of Hydration Shells of Protein Ligand Interfaces and Its Application to Drug Design
Fragment-based drug design exploits
initial screening of low molecular
weight compounds and their concomitant affinity improvement. The multitude
of possible chemical modifications highlights the necessity to obtain
structural information about the binding mode of a fragment. Herein
we describe a novel NMR methodology (LOGSY titration) that allows
the determination of binding modes of low affinity binders in the
protein–ligand interface and reveals suitable ligand positions
for the addition of functional groups that either address or substitute
protein-bound water, information of utmost importance for drug design.
The particular benefit of the methodology and in contrast to conventional
ligand-based methods is the independence of the molecular weight of
the protein under study. The validity of the novel approach is demonstrated
on two ligands interacting with bromodomain 1 of bromodomain containing
protein 4, a prominent cancer target in pharmaceutical industry
An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus
Respiratory infections caused by human rhinovirus are responsible
for severe exacerbations of underlying clinical conditions such as
asthma in addition to their economic cost in terms of lost working
days due to illness. While several antiviral compounds for treating
rhinoviral infections have been discovered, none have succeeded, to
date, in reaching approval for clinical use. We have developed a potent,
orally available rhinovirus inhibitor <b>6</b> that has progressed
through early clinical trials. The compound shows favorable pharmacokinetic
and activity profiles and has a confirmed mechanism of action through
crystallographic studies of a rhinovirus−compound complex.
The compound has now progressed to phase IIb clinical studies of its
effect on natural rhinovirus infection in humans
An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus
Respiratory infections caused by human rhinovirus are responsible
for severe exacerbations of underlying clinical conditions such as
asthma in addition to their economic cost in terms of lost working
days due to illness. While several antiviral compounds for treating
rhinoviral infections have been discovered, none have succeeded, to
date, in reaching approval for clinical use. We have developed a potent,
orally available rhinovirus inhibitor <b>6</b> that has progressed
through early clinical trials. The compound shows favorable pharmacokinetic
and activity profiles and has a confirmed mechanism of action through
crystallographic studies of a rhinovirus−compound complex.
The compound has now progressed to phase IIb clinical studies of its
effect on natural rhinovirus infection in humans
Drugit: Crowd-sourcing molecular design of non-peptidic VHL binders
Given the role of human intuition in current drug design efforts, crowd-sourced \u27citizen scientist\u27 games have the potential to greatly expand the pool of potential drug designers. Here, we introduce ‘Drugit\u27, the small molecule design mode of the online ‘citizen science’ game Foldit. We demonstrate its utility for design with a use case to identify novel binders to the von Hippel Lindau E3 ligase. Several thousand molecule suggestions were obtained from players in a series of 10 puzzle rounds. The proposed molecules were then evaluated by in silico methods and by an expert panel and selected candidates were synthesized and tested. One of these molecules, designed by a player, showed dose-dependent shift perturbations in protein-observed NMR experiments. The co-crystal structure in complex with the E3 ligase revealed that the observed binding mode matched in major parts the player’s original idea. The completion of one full design cycle is a proof of concept for the Drugit approach and highlights the potential of involving citizen scientists in early drug discovery