ABSTRACT
The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Herein, we describe the discovery of the 2,4-diaminonicotinamide derivative 5j, which shows potent inhibitory activity against EGFR del19/T790M/C797S and L858R/T790M/C797S. We also report the structure-activity relationship of the 2,4-diaminonicotinamide derivatives and the co-crystal structure of 5j and EGFR del19/T790M/C797S.
Subject(s)
ErbB Receptors , Lung Neoplasms , Niacinamide , Humans , Drug Resistance, Neoplasm , ErbB Receptors/drug effects , ErbB Receptors/genetics , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , /pharmacology , Niacinamide/analogs & derivatives , Niacinamide/chemistryABSTRACT
A concise synthesis of litseaones A and B, which were isolated from the stem barks of Litsea rubescens and L. pedunculata, is described in this study. Litseaone A was synthesized in just three steps from a known phloroglucinol derivative. The direct conversion of litseaone A into litseaone B was also achieved.
