title: Designing and Testing of Novel Taxanes to Probe the Highly Complex Mechanisms by Which Taxanes Bind to Microtubules and Cause Cytotoxicity to Cancer Cells.
abstract: Our previous work identified an intermediate binding site for taxanes in the microtubule nanopore. The goal of this study was to test derivatives of paclitaxel designed to bind to this intermediate site differentially depending on the isotype of β-tubulin. Since β-tubulin isotypes have tissue-dependent expression--specifically, the βIII isotype is very abundant in aggressive tumors and much less common in normal tissues--this is expected to lead to tubulin targeted drugs that are more efficacious and have less side effects. Seven derivatives of paclitaxel were designed and four of these were amenable for synthesis in sufficient purity and yield for further testing in breast cancer model cell lines. None of the derivatives studied were superior to currently used taxanes, however computer simulations provided insights into the activity of the derivatives. Our results suggest that neither binding to the intermediate binding site nor the final binding site is sufficient to explain the activities of the derivative taxanes studied. These findings highlight the need to iteratively improve on the design of taxanes based on their activity in model systems. Knowledge gained on the ability of the engineered drugs to bind to targets and bring about activity in a predictable manner is a step towards personalizing therapies.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: St George
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ahmed T
authors.initials: AT
authors.lastname: Ayoub
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors.forename: Asok
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Cassandra D M
authors.initials: CD
authors.lastname: Churchill
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Winter
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Klobukowski
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Carol E
authors.initials: CE
authors.lastname: Cass
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ludueña
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada; Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sambasivarao
authors.initials: S
authors.lastname: Damaraju
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D062105:Molecular Docking Simulation; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D058105:Polymerization / Q000187:drug effects; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics; D014404:Tubulin / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel; D017239:Paclitaxel