title: Phosphinic acid-based inhibitors of tubulin polyglutamylases.
abstract: Tubulin is subject to a reversible post-translational modification involving polyglutamylation and deglutamylation of glutamate residues in its C-terminal tail. This process plays key roles in regulating the function of microtubule associated proteins, neuronal development, and metastatic progression. This study describes the synthesis and testing of three phosphinic acid-based inhibitors that have been designed to inhibit both the glutamylating and deglutamylating enzymes. The compounds were tested against the polyglutamylase TTLL7 using tail peptides as substrates (100 μM) and the most potent inhibitor displayed an IC₅₀ value of 150 μM. The incorporation of these compounds into tubulin C-terminal tail peptides may lead to more potent TTLL inhibitors.
authors.affiliation: Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z1.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Liu
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Garnham
authors.forename: Antonina
authors.initials: A
authors.lastname: Roll-Mecak
authors.forename: Martin E
authors.initials: ME
authors.lastname: Tanner
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010721:Phosphinic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D004791:Enzyme Inhibitors; D010721:Phosphinic Acids; D010453:Peptide Synthases; C112698:tubulin polyglutamylase