title: Structure-based design and synthesis of covalent-reversible inhibitors to overcome drug resistance in EGFR.
abstract: 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).
authors.affiliation: Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
authors.forename: Debjit
authors.initials: D
authors.lastname: Basu
authors.affiliation: Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Richters
authors.affiliation: Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany. Electronic address: daniel.rauh@tu-dortmund.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
mesh_terms: D000178:Acrylamides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000178:Acrylamides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C571455:WZ4002; D066246:ErbB Receptors
keywords: Covalent-Reversible Inhibitor; Kinases; Lung cancer; Medicinal chemistry; Receptor tyrosine kinases