title: Synthesis and biological evaluation of pyrimidine-based dual inhibitors of human epidermal growth factor receptor 1 (HER-1) and HER-2 tyrosine kinases.
abstract: A novel series of N(4)-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine-4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases. In contrast to the currently approved HER-2-targeted agent (lapatinib, 1), our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance. The selected compound (19a) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine kinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types: lapatinib-sensitive cell lines (SK-Br3, MDA-MB-175, and N87) and lapatinib-resistant cell lines (MDA-MB-453, H1781, and H1975). The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors, especially HER-2-positive breast/gastric cancer and HER-2-mutated 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: Seok-Jong
authors.initials: SJ
authors.lastname: Kang
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Jung
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Song
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Choi
authors.forename: Joo Yun
authors.initials: JY
authors.lastname: Byun
authors.forename: Han-Jae
authors.initials: HJ
authors.lastname: Lee
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: D000178:Acrylamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D009154:Mutation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D010080:Oxazoles; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C573843:N-((2-(4-amino-6-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide; C512478:EGFR protein, human; C508053:ERBB2 protein, human