Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 24, Pages 6563-6580Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.10.030
Keywords
EGFR tyrosine kinase inhibitors (EGFR-TKI); EGFR T790M/L858R mutant; Structure-based drug design (SBDD); Lamellarin N; Water-soluble analogues
Funding
- Japan Society for the Promotion of Science (JSPS) [26293028, 15K01802]
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Grants-in-Aid for Scientific Research [15K01802, 16K14986, 26293028] Funding Source: KAKEN
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A series of A-ring-modified lamellarin N analogues were designed, synthesized, and evaluated as potential noncovalent inhibitors of the EGFR T790M/L858R mutant, a causal factor in the drug-resistant non-small cell lung cancer. Several water-soluble ammonium- or guanidinium-tethered analogues exhibited good kinase inhibitory activities. The most promising analogue, 14f, displayed an excellent inhibitory profile against the T790M/L858R mutant [IC50 (WT) = 31.8 nM; IC50 (T790M/L858R) = 8.9 nM]. The effects of A-ring-substituents on activity were rationalized by docking studies. (C) 2017 Elsevier Ltd. All rights reserved.
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