title: Discovery of a potent dual EGFR/HER-2 inhibitor L-2 (selatinib) for the treatment of cancer.
abstract: To develop potent dual EGFR/HER-2 inhibitors with improved druggability, a series of new lapatinib analogs were designed and synthesized. Compared with lapatinib, L-2, L-4 and M-6 were more active against BT-474 or NCI-N87 cells. In vivo efficacy studies indicated that L-2 significantly suppressed tumor growth in NCI-N87 (94.8% inhibition) or SK-OV-3 xenograft (85.7% inhibition) without causing significant loss of body weight. And the inhibition rates of lapatinib in the two xenograft models were 89.7% and 78.8%, respectively. Moreover, further studies revealed that the potent in vivo activities of L-2 may be mainly attributed to its superior aqueous solubility and oral bioavailability. In addition, a high-yielding one-pot procedure was developed for the synthesis of lapatinib and its analogs.
authors.affiliation: Qilu Institute of Pharmaceutical Research, Qilu Pharmaceutical Co. Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Chuanwen
authors.initials: C
authors.lastname: Fan
authors.forename: Zongru
authors.initials: Z
authors.lastname: Guo
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Shuyong
authors.initials: S
authors.lastname: Zhao
authors.forename: Shaobo
authors.initials: S
authors.lastname: Yang
authors.forename: Yingying
authors.initials: Y
authors.lastname: Yang
authors.forename: Jianrong
authors.initials: J
authors.lastname: Zhu
authors.forename: Dong
authors.initials: D
authors.lastname: Lin
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C000589305:6-(5-((2-(methylsulfinyl)ethylamino)methyl)furan-2-yl)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-4-quinazolinamine
keywords: EGFR; HER-2; Lapatinib analogs; NCI-N87; SK-OV-3; Selatinib