title: ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2.
abstract: ARRY-334543 is a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters. Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study. Our results demonstrated that ARRY-334543 (1.0 μM) significantly reversed ABCG2-mediated multidrug resistance (MDR) by directly inhibiting the drug efflux function of ABCG2, resulting in the elevated intracellular accumulation of chemotherapeutic drugs in the ABCG2-overexpressing cell lines. In addition, in isolated membranes, ARRY-334543 stimulated ATPase activity and inhibited photolabeling of ABCG2 with [(125)I]-iodoarylazidoprazosin in a concentration-dependent manner indicating that this drug directly interacts at the drug-binding pocket of this transporter. ARRY-334543 (1.0 μM) only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR suggesting that it exhibits high affinity toward ABCG2. Moreover, homology modeling predicted the binding conformation of ARRY-334543 at Arg482 centroid-based grid of ABCG2. However, ARRY-334543 at reversal concentrations did not affect the expression level of ABCG2, AKT and ERK1/2 and regulate the re-localization of ABCG2. We conclude that ARRY-334543 significantly reverses drug resistance mediated by ABCG2.
authors.affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA.
authors.forename: De-Shen
authors.initials: DS
authors.lastname: Wang
authors.forename: Atish
authors.initials: A
authors.lastname: Patel
authors.forename: Hong-May
authors.initials: HM
authors.lastname: Sim
authors.forename: Yun-Kai
authors.initials: YK
authors.lastname: Zhang
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Wang
authors.forename: Rishil J
authors.initials: RJ
authors.lastname: Kathawala
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Rui-Hua
authors.initials: RH
authors.lastname: Xu
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D013844:Thiazoles / Q000008:administration & dosage*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D018739:Oncogene Proteins v-erbB; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013844:Thiazoles; C116614:ABCG2 protein, human; C000595244:ARRY-334543; C508053:ERBB2 protein, human
keywords: ABCG2; ARRY-334543; LUNG CANCER; MULTIDRUG RESISTANCE; TYROSINE KINASE INHIBITOR