WD repeat domain 5 (WDR5) is a core scaffolding component of many multiprotein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is a component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin at tumor-critical target genes. As a part of these complexes, WDR5 plays a role in sustaining oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule inhibitors of the WDR5-interaction (WIN) site and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P
7
units through structure-based design and address the limitations of our previous series of small-molecule inhibitors. Importantly, our lead compounds exhibit enhanced on-target potency, excellent oral pharmacokinetic (PK) profiles, and potent dose-dependent in vivo efficacy in a mouse MV4:11 subcutaneous xenograft model by oral dosing. Furthermore, these in vivo probes show excellent tolerability under a repeated high-dose regimen in rodents to demonstrate the safety of the WDR5 WIN-site inhibition mechanism. Collectively, our results provide strong support for WDR5 WIN-site inhibitors to be utilized as potential anticancer therapeutics.
WD
repeat domain 5 (WDR5) is a nuclear scaffolding protein that
forms many biologically important multiprotein complexes. The WIN
site of WDR5 represents a promising pharmacological target in a variety
of human cancers. Here, we describe the optimization of our initial
WDR5 WIN-site inhibitor using a structure-guided pharmacophore-based
convergent strategy to improve its druglike properties and pharmacokinetic
profile. The core of the previous lead remained constant while a focused
SAR effort on the three pharmacophore units was combined to generate
a new in vivo lead series. Importantly, this new
series of compounds has picomolar binding affinity, improved cellular
antiproliferative activity and selectivity, and increased kinetic
aqueous solubility. They also exhibit a desirable oral pharmacokinetic
profile with manageable intravenous clearance and high oral bioavailability.
Thus, these new leads are useful probes toward studying the effects
of WDR5 inhibition.
A simple one-dimensional 1H NMR experiment that quantifies
protein bound to gold nanoparticles has been developed for upper-division
biochemistry and physical chemistry students. This laboratory experiment
teaches the basics of NMR techniques, which is a highly effective
tool in protein studies and supports students to understand the concepts
of NMR spectroscopy and nanoparticle–protein interactions.
Understanding the interactions of gold nanoparticles (AuNPs) with
biological macromolecules is becoming increasingly important as interest
in the clinical use of nanoparticles has been on the rise. Applications
in drug delivery, biosensing, diagnostics, and enhanced imaging are
all tangible possibilities with a better understanding of AuNP–protein
interactions. The ability to use AuNPs as biosensors for drug delivery
methods in cellular uptake is dependent on the amount of protein that
is able to bind to the surface of the nanoparticle. This laboratory
experiment solidifies concepts such as quantitative NMR spectroscopy
while reinforcing precision laboratory titrations. Students learn
how 1H proton NMR spectra can be used to measure free protein
in solution and protein bound to AuNPs. A simple formula is used to
determine the binding capacity of the nanoparticle. This analysis
helps students to understand the impact of nanoparticle–protein
interactions, and it allows them to conceptualize macromolecular binding
using NMR spectroscopy.
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