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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• WD repeat domain 5 (WDR5) is a nuclear scaffolding protein involved in crucial multiprotein complexes.
• The WDR5 WIN site is a validated pharmacological target for various human cancers.

Purpose of the Study:

• To optimize initial WDR5 WIN-site inhibitors.
• To enhance druglike properties and pharmacokinetic profiles of WDR5 inhibitors.
• To develop novel chemical probes for studying WDR5 inhibition.

Main Methods:

• Employed a structure-guided, pharmacophore-based convergent strategy.
• Focused structure-activity relationship (SAR) studies on three key pharmacophore units.
• Maintained the core structure of the previous lead compound.

Main Results:

• Generated a new series of in vivo lead compounds.
• Achieved picomolar binding affinity for WDR5.
• Demonstrated improved cellular antiproliferative activity and selectivity.
• Enhanced kinetic aqueous solubility and oral pharmacokinetic profiles, including high oral bioavailability.

Conclusions:

• The optimized WDR5 inhibitors exhibit potent activity and favorable drug-like properties.
• These novel compounds serve as valuable chemical probes for investigating WDR5's role in cancer.
• The findings support WDR5 as a viable therapeutic target in oncology.