Optimization of α-Fluoro, β-Heteroaryl Acrylamide Warheads for KRAS^G12C Active-State Inhibition

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Pharmacology

Background:

• KRAS^G12C mutations drive various cancers.
• Targeting KRAS^G12C with covalent inhibitors is a key therapeutic strategy.
• Novel warhead designs are needed to overcome resistance and improve efficacy.

Purpose of the Study:

• To investigate the reactivity and pharmaceutical properties of α-fluoro, β-heteroaryl acrylamides as covalent warheads.
• To understand the structure-activity relationships governing warhead reactivity and drug-like properties.
• To identify a lead compound for KRAS^G12C-driven cancers.

Main Methods:

• Synthesis and characterization of novel acrylamide derivatives.
• In vitro assays to assess warhead reactivity (vinylogous S_NAr) and drug properties (potency, permeability, efflux).
• In vivo efficacy studies in a mouse xenograft model.

Main Results:

• The novel acrylamides exhibit α-position reactivity via vinylogous S_NAr, distinct from traditional β-addition.
• Warhead reactivity is influenced by heterocycle basicity and electrophilicity.
• Lead compound demonstrated low clearance and robust anti-tumor efficacy in vivo.

Conclusions:

• α-Fluoro, β-heteroaryl acrylamides represent a promising class of covalent warheads for KRAS^G12C inhibition.
• Understanding warhead chemistry is crucial for optimizing drug properties and in vivo performance.
• The identified lead molecule warrants further development for cancer therapy.