title: A platinum-based hybrid drug design approach to circumvent acquired resistance to molecular targeted tyrosine kinase inhibitors.
abstract: Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted.
authors.affiliation: Department of Chemistry, Faculty of Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Wei
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Poon
authors.affiliation: Department of Chemistry, Faculty of Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Fei
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Amy S M
authors.initials: AS
authors.lastname: Lam
authors.affiliation: Department of Chemistry, Faculty of Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Steve C F
authors.initials: SC
authors.lastname: Au-Yeung
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000494:pharmacology; D001923:Brain Chemistry; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D002945:Cisplatin; C452423:vandetanib