A platinum-based hybrid drug design approach to circumvent acquired resistance to molecular targeted tyrosine kinase inhibitors

• DOI: 10.1038/srep25363
• Publication Date: 2016-05-06T09:09:28Z
• Authors: Yuming Wei; Daniel C. Poon; Rong Fei; Amy S. M. Lam; Steve C. F. Au-Yeung; Kenneth K. W. To
• Keywords: Brain Chemistry; 0303 health sciences; Lung Neoplasms; Antineoplastic Agents; Xenograft Model Antitumor Assays; Article; 3. Good health; Erlotinib Hydrochloride; Mice; 03 medical and health sciences; Piperidines; Drug Resistance, Neoplasm; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Mutation; Quinazolines; Animals; Humans; Molecular Targeted Therapy; Cisplatin; K562 Cells; Protein Kinase Inhibitors

AbstractThree 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.