The discovery of a potent and selective third-generation EGFR kinase inhibitor as a therapy for EGFR L858R/T790M double mutant non-small cell lung cancer

• Published in: European journal of medicinal chemistry Vol. 183; pp. 111709 - 111722
• Main Authors: An, Baijiao, Pan, Tingting, Hu, Jinhui, Pang, Yanqing, Huang, Ling, Chan, Albert S.C., Li, Xingshu, Yan, Jun
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.12.2019; Elsevier
• Subjects: Acrylamides - chemistry; Acrylamides - pharmacokinetics; Aniline Compounds - chemistry; Aniline Compounds - pharmacokinetics; Animals; Anti-Tumor activity; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Apoptosis; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; Humans; L858R/T790M double mutant; Life Sciences & Biomedicine; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Male; Molecular Targeted Therapy; Mutation; Non-small cell lung cancer (NSCLC); Pharmacokinetic properties; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Science & Technology; Anti-Tumor activity; L858R/T790M double mutant; Pharmacokinetic properties; Non-small cell lung cancer (NSCLC); Apoptosis; DESIGN; OSIMERTINIB; T790M-MEDIATED RESISTANCE; GROWTH-FACTOR RECEPTOR; MUTATIONS; DERIVATIVES; EXPRESSION; AZD9291
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111709

A new series of AZD9291 (osimertinib) derivatives containing a sulfoxide side chain at the C-4 position of an aniline moiety were designed, synthesized and evaluated. Among these derivatives, the chiral sulfoxide derivative (−)-4i exhibited excellent inhibition of EGFR kinase activity and L858R/T790M double mutant cell proliferation, with IC50 values of 4.10 nM and 10 nM, respectively. A mechanism study elucidated that (−)-4i induced cell apoptosis and reduced phosphorylation of EGFR and AKT in a dose-dependent manner. Furthermore, (−)-4i exhibited very little apparent toxicity toward three non-tumorigenic cell lines and was less toxic than AZD9291. Moreover, the remarkable exposure (AUC0-inf: 1294.74 h ng/mL), oral bioavailability (73.69%), and relatively shorter half-life (t1/2 = 1.12 h) of (−)-4i displayed its favorable pharmacokinetic properties. Finally, the antitumor activity of (−)-4i in vivo resulted in a significant reduction of the tumor volume (TGI: 94.30%). Altogether, these results suggest that (−)-4i warrants further investigation in Non-Small cell lung cancer (NSCLC) therapy. [Display omitted] •Osimertinib derivatives containing sulfoxide side chain at C-4 position of an aniline moiety were synthesized.•Most compounds exhibited excellent EGFR kinase inhibition activity. Most compounds displayed anti-proliferative activity towards L858R/T790M double mutant cell lines.•(−)-4i displayed favorable pharmacokinetic properties.