title: Chimeric microtubule disruptors.
abstract: A chimeric approach is used to discover microtubule disruptors with excellent in vitro activity and oral bioavailability; a ligand-protein interaction with carbonic anhydrase that enhances bioavailability is characterised by protein X-ray crystallography. Dosing of a representative chimera in a tumour xenograft model confirms the excellent therapeutic potential of the class.
authors.affiliation: Medicinal Chemistry & Sterix Ltd., Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jourdan
authors.forename: Meriel R
authors.initials: MR
authors.lastname: Kimberley
authors.forename: Gyles E
authors.initials: GE
authors.lastname: Cozier
authors.forename: Nethaji
authors.initials: N
authors.lastname: Thiyagarajan
authors.forename: Chloe
authors.initials: C
authors.lastname: Stengel
authors.forename: Sandra
authors.initials: S
authors.lastname: Regis-Lydi
authors.forename: Paul A
authors.initials: PA
authors.lastname: Foster
authors.forename: Simon P
authors.initials: SP
authors.lastname: Newman
authors.forename: K Ravi
authors.initials: KR
authors.lastname: Acharya
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrandis
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D050257:Tubulin Modulators / Q000737:chemistry* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D008024:Ligands; D050257:Tubulin Modulators; D024402:Carbonic Anhydrase II