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 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

Automated summary

The study successfully optimized the drug structure of WDR5, improving its druglike properties and pharmacokinetic profile. A new series of compounds with strong binding affinity and high selectivity were generated, serving as useful tools for WDR5 inhibition research.