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

摘要

WD repeat domain 5 (WDR5) is a nuclear scaffolding protein that forms many biologically important multiproteincomplexes. The WIN site of WDR5 represents a promising pharmacological target in a variety of human cancers. Here, we describethe optimization of our initial WDR5 WIN-site inhibitor using a structure-guided pharmacophore-based convergent strategy toimprove its druglike properties and pharmacokinetic profile. The core of the previous lead remained constant while a focused SAReffort on the three pharmacophore units was combined to generate a newin vivolead series. Importantly, this new series ofcompounds has picomolar binding affinity, improved cellular antiproliferative activity and selectivity, and increased kinetic aqueoussolubility. They also exhibit a desirable oral pharmacokinetic profile with manageable intravenous clearance and high oralbioavailability. Thus, these new leads are useful probes toward studying the effects of WDR5 inhibition