Abstract
Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Drug Discovery
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ErbB Receptors* / antagonists & inhibitors
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ErbB Receptors* / genetics
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ErbB Receptors* / metabolism
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Exons*
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Mice
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Mutagenesis, Insertional
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Mutation
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Protein Kinase Inhibitors* / chemical synthesis
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Protein Kinase Inhibitors* / chemistry
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Protein Kinase Inhibitors* / pharmacology
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Protein Kinase Inhibitors* / therapeutic use
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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ErbB Receptors
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EGFR protein, human
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Protein Kinase Inhibitors
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Antineoplastic Agents