Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 12, Pages 2767-2780Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.04.038
Keywords
Kinases; Medicinal chemistry; Receptor tyrosine kinases; Lung cancer; Covalent-Reversible Inhibitor
Funding
- German Federal State North Rhine Westphalia (NRW)
- European Union (European Regional Development Fund: Investing In Your Future, NEGECA)
- German Federal Ministry for Education and Research (NGFNPlus and e:Med) [BMBF 01GS08104, 01ZX1303C]
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The clinical success of covalent kinase inhibitors in the treatment of EGFR-dependent non-small cell lung cancer (NSCLC) has rejuvenated the appreciation of reactive small molecules. Acquired drug resistance against first-line EGFR inhibitors remains the major bottleneck in NSCLC and is currently addressed by the application of fine-tuned covalent drugs. Here we report the design, synthesis and biochemical evaluation of a novel class of EGFR inhibitors with a covalent yet reversible warhead. A series of WZ4002 analogs, derived from anilinopyrimidine and 3-substituted-2-cyanoacrylamide scaffolds, exhibit strong and selective inhibitory activity against clinically relevant EGFR(L858R) and EGFR(L858R/T790M). (C) 2015 Elsevier Ltd. All rights reserved.
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