The <i>Pthaladyns</i>: GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening

Odell, Luke R.; Howan, Dian Herlinda Octorina; Gordon, Christopher P.; Robertson, Mark J.; Chau, Ngoc; Mariana, Anna; Whiting, Ainslie; Abagyan, Ruben; Daniel, James; Gorgani, Nick N.; Robinson, Phillip J.; McCluskey, Adam

doi:10.1021/jm100442u

Cited by 49 publications

(53 citation statements)

References 59 publications

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“…Quantitative high-throughput receptor-mediated endocytosis (RME) assays were performed as previously described (Hill et al, 2009;Odell et al, 2010) using Transferrin (Tfn) conjugated to Texas Red in untreated and siRNA-transfected HeLa cells for 10 min. Cells were then washed with ice-cold PBS and acid washed (0.2 M acetic acid/0.5 M NaCl, pH 2.8) for 15 min on ice.…”

Section: Endocytosis Assaymentioning

confidence: 99%

SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis

Maggie

Chircop

2012

Journal of Cell Science

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SummaryMitosis involves considerable membrane remodelling and vesicular trafficking to generate two independent cells. Consequently, endocytosis and endocytic proteins are required for efficient mitotic progression and completion. Several endocytic proteins also participate in mitosis in an endocytosis-independent manner. Here, we report that the sorting nexin 9 (SNX9) subfamily members -SNX9, SNX18 and SNX33 -are required for progression and completion of mitosis. Depletion of any one of these proteins using siRNA induces multinucleation, an indicator of cytokinesis failure, as well as an accumulation of cytokinetic cells. Time-lapse microscopy on siRNA-treated cells revealed a role for SNX9 subfamily members in progression through the ingression and abscission stages of cytokinesis. Depletion of these three proteins disrupted MRLC S19 localization during ingression and recruitment of Rab11-positive recycling endosomes to the intracellular bridge between nascent daughter cells. SNX9 depletion also disrupted the localization of Golgi during cytokinesis. Endocytosis of transferrin was blocked during cytokinesis by depletion of the SNX9 subfamily members, suggesting that these proteins participate in cytokinesis in an endocytosis-dependent manner. In contrast, depletion of SNX9 did not block transferrin uptake during metaphase but did delay chromosome alignment and segregation, suggesting that SNX9 plays an additional non-endocytic role at early mitotic stages. We conclude that SNX9 subfamily members are required for mitosis through both endocytosis-dependent and -independent processes.

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Section: Endocytosis Assaymentioning

confidence: 99%

SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis

Maggie

Chircop

2012

Journal of Cell Science

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“…30 Each series thus far has targeted many of dynamin's four domains: the pleckstrin homology, the assembly domain, the proline-rich domain, and the GTP binding domain. Other reported dynamin inhibitors include dynasore, antipsychotics, and selective serotonin reuptake inhibitors.…”

Section: Scheme 1 Amentioning

confidence: 99%

“…C10 and D10 are among the most potent RME inhibitors reported, only surpassed by Dynole 34-2 (IC 50(RME) ∼ 5.0 μM). 28,30,36 The development of the Rhodadyn series adds another chemical biology probe to the expanding palette of dynamin inhibitors. …”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

The Rhodadyns, a New Class of Small Molecule Inhibitors of Dynamin GTPase Activity

Robertson

Hadzic

Ambrus

et al. 2012

ACS Med. Chem. Lett.

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Six focused rhodanine-based libraries, 60 compounds in total, were synthesized and evaluated as potential dynamin I GTPase inhibitors. Twenty-six were more potent than the lead compound with 13 returning IC 50 values ≤10 μM, making the Rhodadyn series among the most active dynamin inhibitors reported. Two analogues were highly effective at blocking receptor-mediated endocytosis: C10 and D10 with IC 50(RME) = 7.0 ± 2.2 and 5.9 ± 1.0 μM, respectively. These compounds are equipotent with the best reported in-cell dynamin inhibitors. KEYWORDS: dynamin inhibition, Knoevengal condensation, rhodanine D ynamin is a 100kD GTPase, 1 with three closely related mammalian isoforms: dynamin I (dynI), 2,3 dynamin II (dynII), 4 and dynamin III (dynIII). 5 Each isoform has a different number of spliced variants: dynI has eight, dynII has four, and dynIII has thirteen.6 Each may have different regulatory mechanisms at distinct locations within the cell or be involved in the cellular localization of dynamin. 7,8 The best-characterized superfamily member is dynI, exclusively expressed in brain and neuronal tissue. DynI is a key component of the synaptic vesicle (SV) recycling, which in turn is essential for the maintenance of neurotransmission, serving to retrieve empty SVs for refilling and reuse. 6,9,10 SV recycling is a specialized, rapid local endocytic recycling, considered to be a specialized form of receptor-mediated endocytosis (RME). 6−8Dynamin is also involved in clathrin-independent endocytosis, phagocytosis, and caveolae internalization. It has been implicated in cellular processes such as vesicle trafficking, Golgi function, organelle division, and mitochondria and chloroplast biogenesis. 7,8,11 Dynamin facilitates cell migration and invasion and potentially plays an important role in cell growth, cell spreading, and neurite outgrowth. 12Targeting endocytosis and trafficking defects through the dynamin inhibition represents a novel strategy for the treatment of many diseases such as neurological (e.g., epilepsy), viral, and bacterial (which enter cells via clathrin-medicated endocytosis) infections.13−15 Disruption of the cellular transport process has been linked to over 100 diseases involving endocytosis and intracellular trafficking defects.

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“…24 is found to be the most active in the series (Gordon et al, 2013). Odell et al (2010) have reported series of compounds such as pthaladyns based on the homology model for the GTP-binding domain of human DNM1. Pthaladyan-23 was found to be a potent inhibitor of DNM1-mediated synaptic vesicle endocytosis in brain synaptosomes (Odell et al, 2010).…”

Section: Dynamin Function and Ligandsmentioning

confidence: 99%

“…Odell et al (2010) have reported series of compounds such as pthaladyns based on the homology model for the GTP-binding domain of human DNM1. Pthaladyan-23 was found to be a potent inhibitor of DNM1-mediated synaptic vesicle endocytosis in brain synaptosomes (Odell et al, 2010). Hill et al (2004Hill et al ( , 2005Hill et al ( , 2009 have reported amines and Dynoles for the inhibition of dynamin-mediated endocytosis.…”

Section: Dynamin Function and Ligandsmentioning

confidence: 99%

Dynamin Functions and Ligands: Classical Mechanisms Behind

2016

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Dynamin is a GTPase that plays a vital role in clathrin-dependent endocytosis and other vesicular trafficking processes by acting as a pair of molecular scissors for newly formed vesicles originating from the plasma membrane. Dynamins and related proteins are important components for the cleavage of clathrin-coated vesicles, phagosomes, and mitochondria. These proteins help in organelle division, viral resistance, and mitochondrial fusion/fission. Dysfunction and mutations in dynamin have been implicated in the pathophysiology of various disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Charcot-Marie-Tooth disease, heart failure, schizophrenia, epilepsy, cancer, dominant optic atrophy, osteoporosis, and Down's syndrome. This review is an attempt to illustrate the dynamin-related mechanisms involved in the above-mentioned disorders and to help medicinal chemists to design novel dynamin ligands, which could be useful in the treatment of dynamin-related disorders.

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The Pthaladyns: GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening

Cited by 49 publications

References 59 publications

SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis

SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis

The Rhodadyns, a New Class of Small Molecule Inhibitors of Dynamin GTPase Activity

Dynamin Functions and Ligands: Classical Mechanisms Behind

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