Abstract
Because of the development of drug-resistance mutations, particularly the "gatekeeper" threonine(790)-to-methionine(790) (T790M) mutation in the ATP-binding pocket of the epidermal growth factor receptor (EGFR), the current generation of EGFR tyrosine kinase inhibitors lost their clinical efficacy. Recently, a large number of small-molecule inhibitors with striking inhibitory potency against EGFR mutants with the T790M change have been identified. In particular, the inhibitors rociletinib and osimertinib, which can selectively target both sensitizing mutations and the T790M resistance while sparing the wild-type (WT) form of the receptor, have been designated as breakthrough therapies in the treatment of mutant non-small-cell lung cancer (NSCLC) by the U.S. FDA in 2014. We hope that this review on the small-molecule EGFR T790M inhibitors, along with their discovery strategies, will assist in the design of future T790M-containing EGFR inhibitors with high levels of selectivity over WT EGFR, broad kinase selectivity, and desirable physicochemical properties.
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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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / metabolism
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / pathology
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Mice
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Models, Molecular
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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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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Pyridones / chemical synthesis
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Pyridones / chemistry
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Pyridones / pharmacology*
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyridones
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Small Molecule Libraries
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EGFR protein, human
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ErbB Receptors