Discovery and Optimization of a WRN Helicase Inhibitor Series through Structure-Guided Drug Design from a Covalent...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• WRN helicase inhibition is a promising strategy for cancers with DNA repair deficiencies, particularly microsatellite instability (MSI).
• Targeting WRN offers a therapeutic avenue for specific tumor types.

Purpose of the Study:

• To discover and optimize novel covalent inhibitors of WRN helicase.
• To develop a potent and safe clinical candidate for MSI-positive tumors.

Main Methods:

• Structure-based design and covalent fragment investigation were employed.
• In vitro assays assessed cellular potency (p21 induction, HCT116 CTG viability), warhead reactivity, and ADME properties.
• In vivo studies evaluated pharmacokinetics in rats and dogs.

Main Results:

• A novel series of covalent WRN helicase inhibitors was identified.
• Optimized compounds demonstrated nanomolar cellular potency.
• Lead compound WC-2 exhibited excellent potency, low GSH reactivity, good stability, oral bioavailability, and long half-lives in vivo.
• WC-2 showed favorable ADME properties and pharmacokinetics.

Conclusions:

• WC-2 is a potent WRN helicase inhibitor with promising drug-like characteristics.
• This compound has potential as a next-generation, low-dose clinical candidate for treating MSI-classified tumors.