Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization

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.