title: Discovery of a novel Her-1/Her-2 dual tyrosine kinase inhibitor for the treatment of Her-1 selective inhibitor-resistant non-small cell lung cancer.
abstract: A novel series of (S)-1-acryloyl-N-[4-(arylamino)-7-(alkoxy)quinazolin-6-yl]pyrrolidine-2-carboxamides were synthesized and evaluated as Her-1/Her-2 dual inhibitors. In contrast to the Her-1 selective inhibitors, our novel compounds are irreversible inhibitors of Her-1 and Her-2 tyrosine kinases with the potential to overcome clinically relevant, mutation-induced drug resistance. The selected compounds (19c, 19d) showed excellent EGFR inhibition activity even toward the T790M mutation of Her-1 tyrosine kinase with excellent selectivity. The excellent pharmacokinetic profiles of these compounds in rats and their robust in vivo efficacy in an A431 xenograft model clearly demonstrate that they merit further investigation as novel therapeutic agents for EGFR-targeting treatment of solid tumors, especially Her-1 selective inhibitor-resistant non-small cell lung cancer.
authors.affiliation: Department of Drug Discovery, Hanmi Research Center, 377-1 Yeongcheon-ri, Dongtan-myeon, Hwaseong, Gyeonggi-do, 445-813, Korea.
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Cha
authors.forename: Kwang-Ok
authors.initials: KO
authors.lastname: Lee
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Chang Gon
authors.initials: CG
authors.lastname: Lee
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Song
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Gwan Sun
authors.initials: GS
authors.lastname: Lee
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.forename: Maeng Sup
authors.initials: MS
authors.lastname: Kim
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D011759:Pyrrolidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C545548:1-acryloyl-N-(4-(3-chloro-2,4-difluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)pyrrolidine-2-carboxamide; C545547:1-acryloyl-N-(4-(3-chloro-2-fluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)pyrrolidine-2-carboxamide