Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether and biaryl as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo.
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Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations.
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Article Synopsis
- - Drug resistance in EGFR-mutant non-small cell lung cancer (NSCLC) is complicated by mechanisms like pathway reactivation and fusion of receptor tyrosine kinases (RTKs), leading to challenges in treatment with tyrosine kinase inhibitors (TKIs).
- - A study involving multiple institutions analyzed 27 patients with RTK fusions identified through genetic testing, focusing on their response to dual TKI therapy, with results showing a 24% objective response rate and an 80% disease control rate overall.
- - The majority of patients had ALK or RET fusions, and those who received dual TKI treatment had a slightly lower response rate (21.4%) but no new side effects were reported, suggesting this approach
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