Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Molecular Pharmacology

Background:

• WD repeat domain 5 (WDR5) is a crucial cofactor for MYC and regulates ribosome protein gene transcription.
• WDR5 is a validated anti-cancer target for solid and hematological malignancies.
• Previous studies identified dihydroisoquinolinone-based WDR5 WIN-site inhibitors with preclinical efficacy.

Purpose of the Study:

• To optimize the bicyclic core of WDR5 WIN-site inhibitors.
• To discover novel WDR5 inhibitors with enhanced potency and physicochemical properties.
• To explore alternative scaffolds for WDR5 inhibition.

Main Methods:

• Structure-based drug design utilizing X-ray crystallography.
• Synthesis and optimization of novel benzoxazepinone-based compounds.
• In vitro cellular assays to evaluate compound potency and selectivity.

Main Results:

• Identified 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one as a novel scaffold for WDR5 inhibitors.
• Designed partially saturated bicyclic P7 units for improved inhibitor properties.
• Benzoxazepinone-based inhibitors demonstrated increased cellular potency and selectivity over previous compounds.
• Achieved favorable physicochemical properties in the novel inhibitor series.

Conclusions:

• The benzoxazepinone scaffold represents a promising alternative for developing potent WDR5 WIN-site inhibitors.
• Optimized WDR5 inhibitors exhibit improved cellular activity and drug-like properties.
• These findings support the advancement of WDR5 inhibitors as novel anti-cancer therapeutics.