2. Academic Validation
  3. Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain

Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain

  • J Med Chem. 2017 Jan 12;60(1):349-361. doi: 10.1021/acs.jmedchem.6b01422.
Luke R Odell 1,  Mohammed K Abdel-Hamid 1 2,  Timothy A Hill 1,  Ngoc Chau 3,  Kelly A Young 1,  Fiona M Deane 1,  Jennette A Sakoff 4,  Sofia Andersson 5,  James A Daniel 3,  Phillip J Robinson 3,  Adam McCluskey 1
Affiliations

Affiliations

  • 1 Chemistry, School of Environmental and Life Sciences, The University of Newcastle , Callaghan, New South Wales 2308, Australia.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University , Assiut 71526, Egypt.
  • 3 Children's Medical Research Institute, The University of Sydney , 214 Hawkesbury Road, Westmead New South Wales 2145, Australia.
  • 4 Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Newcastle Hospital , Edith Street, Waratah, 2298, New South Wales Australia.
  • 5 Department of Biology and Chemical Engineering, Mälardalens University , Box 325, S-631 05, Eskilstuna, Sweden.
PMID: 27997171 DOI: 10.1021/acs.jmedchem.6b01422
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 H1 and H2, melanocortin, melatonin, muscarinic M1 and M3, neurokinin, opioid KOP and serotonin receptors.

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