title: A novel two mode-acting inhibitor of ABCG2-mediated multidrug transport and resistance in cancer chemotherapy.
abstract: BACKGROUND
  Multidrug resistance (MDR) is a major problem in successful treatment of cancers. Human ABCG2, a member of the ATP-binding cassette transporter superfamily, plays a key role in MDR and an important role in protecting cancer stem cells. Knockout of ABCG2 had no apparent adverse effect on the mice. Thus, ABCG2 is an ideal target for development of chemo-sensitizing agents for better treatment of drug resistant cancers and helping eradicate cancer stem cells.
  Using rational screening of representatives from a chemical compound library, we found a novel inhibitor of ABCG2, PZ-39 (N-(4-chlorophenyl)-2-[(6-{[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1,3-benzothiazol-2-yl)sulfanyl]acetamide), that has two modes of actions by inhibiting ABCG2 activity and by accelerating its lysosome-dependent degradation. PZ-39 has no effect on ABCB1 and ABCC1-mediated drug efflux, resistance, and their expression, indicating that it may be specific to ABCG2. Analyses of its analogue compounds showed that the pharmacophore of PZ-39 is benzothiazole linked to a triazine ring backbone.
  
  
  CONCLUSIONS
  Unlike any previously known ABCG2 transporter inhibitors, PZ-39 has a novel two-mode action by inhibiting ABCG2 activity, an acute effect, and by accelerating lysosome-dependent degradation, a chronic effect. PZ-39 is potentially a valuable probe for structure-function studies of ABCG2 and a lead compound for developing therapeutics targeting ABCG2-mediated MDR in combinational cancer chemotherapy.
authors.affiliation: Department of Pharmacology and Toxicology, University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Zizheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.forename: Youyun
authors.initials: Y
authors.lastname: Yang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Li
authors.forename: Junkang
authors.initials: J
authors.lastname: Xu
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Zhang
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008942:Mitoxantrone / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy*; D011487:Protein Conformation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects
chemical_list: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C419353:ABCG1 protein, human; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1