Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations.

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Epidermal growth factor receptor (EGFR) inhibitors have advanced cancer treatment.
• A significant unmet need exists for inhibitors targeting EGFR Exon20 insertion (Ex20Ins) mutations.
• Existing therapies often lack selectivity, impacting wild-type (WT) EGFR.

Purpose of the Study:

• To discover and optimize novel chemical series for potent and selective EGFR Ex20Ins inhibition.
• To develop brain-penetrant inhibitors that spare WT EGFR.
• To address challenges like aldehyde oxidase (AO) metabolism and achieve favorable pharmacokinetic properties.

Main Methods:

• Structure-based drug design was employed to optimize lead compounds.
• Two chemical series, ether 23 and biaryl 36, were explored.
• Structure-activity relationship (SAR) studies guided optimization for potency, selectivity, and reduced metabolism.

Main Results:

• Ether 23 and biaryl 36 were identified as potent and selective inhibitors of Ex20Ins mutants.
• Compounds demonstrated brain penetrance and maintained a selectivity margin over WT EGFR.
• Optimization successfully reduced aldehyde oxidase (AO) metabolism, a human clearance risk.

Conclusions:

• Compounds 23 and 36 represent promising drug candidates for EGFR Ex20Ins-driven cancers.
• The developed inhibitors show efficacy in preclinical models with a favorable safety margin.
• This work advances the development of targeted therapies for a challenging subset of lung cancer.