title: Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain.
abstract: The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50= 10.6 ± 1.3 to 1.6 ± 0.3 μM) and CME (IC50(CME)= 65.9 ± 7.7 to 3.7 ± 1.1 mM), which makes this series among the more potent inhibitors of dynamin and CME yet reported. In CME and growth inhibition cell-based assays, the data obtained was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-target effects at the cholecystokinin, dopamine D2, histamine H1and H2, melanocortin, melatonin, muscarinic M1and M3, neurokinin, opioid KOP and serotonin receptors.
authors.affiliation: Chemistry, School of Environmental and Life Sciences, The University of Newcastle , Callaghan, New South Wales 2308, Australia.
authors.forename: Luke R
authors.identifier: 0000-0001-7658-5103
authors.initials: LR
authors.lastname: Odell
authors.affiliation: Chemistry, School of Environmental and Life Sciences, The University of Newcastle , Callaghan, New South Wales 2308, Australia.|Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University , Assiut 71526, Egypt.
authors.forename: Mohammed K
authors.initials: MK
authors.lastname: Abdel-Hamid
authors.affiliation: Chemistry, School of Environmental and Life Sciences, The University of Newcastle , Callaghan, New South Wales 2308, Australia.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hill
authors.affiliation: Children's Medical Research Institute, The University of Sydney , 214 Hawkesbury Road, Westmead New South Wales 2145, Australia.
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.affiliation: Chemistry, School of Environmental and Life Sciences, The University of Newcastle , Callaghan, New South Wales 2308, Australia.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Young
authors.affiliation: Chemistry, School of Environmental and Life Sciences, The University of Newcastle , Callaghan, New South Wales 2308, Australia.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Deane
authors.affiliation: Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Newcastle Hospital , Edith Street, Waratah, 2298, New South Wales Australia.
authors.forename: Jennette A
authors.initials: JA
authors.lastname: Sakoff
authors.affiliation: Department of Biology and Chemical Engineering, Mälardalens University , Box 325, S-631 05, Eskilstuna, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Andersson
authors.affiliation: Children's Medical Research Institute, The University of Sydney , 214 Hawkesbury Road, Westmead New South Wales 2145, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Daniel
authors.affiliation: Children's Medical Research Institute, The University of Sydney , 214 Hawkesbury Road, Westmead New South Wales 2145, Australia.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.affiliation: Chemistry, School of Environmental and Life Sciences, The University of Newcastle , Callaghan, New South Wales 2308, Australia.
authors.forename: Adam
authors.identifier: 0000-0001-7125-863X
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D001667:Binding, Competitive; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D034284:Dynamin I / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D013058:Mass Spectrometry; D000070539:Pleckstrin Homology Domains / Q000187:drug effects*; D066244:Proton Magnetic Resonance Spectroscopy; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D034284:Dynamin I; C030986:pyrimidine