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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Jun 6

PMID 24900478

Citations 12

Authors

Mark J Robertson

Gordana Hadzic

Joseph Ambrus

D Yuri Pome

Emily Hyde

Ainslie Whiting

Anna Mariana

Lisa von Kleist

Ngoc Chau

Volker Haucke

Phillip J Robinson

Adam McCluskey

Affiliations

Soon will be listed here.

Abstract

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 IC50 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 IC50(RME) = 7.0 ± 2.2 and 5.9 ± 1.0 μM, respectively. These compounds are equipotent with the best reported in-cell dynamin inhibitors.

Citing Articles

The Chemical Inhibitors of Endocytosis: From Mechanisms to Potential Clinical Applications.

Szewczyk-Roszczenko O, Roszczenko P, Shmakova A, Finiuk N, Holota S, Lesyk R Cells. 2023; 12(18).

PMID: 37759535 PMC: 10527932. DOI: 10.3390/cells12182312.

The sulfonadyns: a class of aryl sulfonamides inhibiting dynamin I GTPase and clathrin mediated endocytosis are anti-seizure in animal models.

Odell L, Jones N, Chau N, Robertson M, Ambrus J, Deane F RSC Med Chem. 2023; 14(8):1492-1511.

PMID: 37593570 PMC: 10429932. DOI: 10.1039/d2md00371f.

Mechanistic-Based Classification of Endocytosis-Related Inhibitors: Does It Aid in Assigning Drugs against SARS-CoV-2?.

Hessien M, Donia T, Tabll A, Adly E, Abdelhafez T, Attia A Viruses. 2023; 15(5).

PMID: 37243127 PMC: 10222743. DOI: 10.3390/v15051040.

Prodrugs of the Archetypal Dynamin Inhibitor Bis-T-22.

Odell L, Robertson M, Young K, McGeachie A, Quan A, Robinson P ChemMedChem. 2022; 17(24):e202200400.

PMID: 36351775 PMC: 10947042. DOI: 10.1002/cmdc.202200400.

Insight into the role of clathrin-mediated endocytosis inhibitors in SARS-CoV-2 infection.

Sami Alkafaas S, Abdallah A, Ghosh S, Loutfy S, Samy ElKafas S, Abdel Fattah N Rev Med Virol. 2022; 33(1):e2403.

PMID: 36345157 PMC: 9877911. DOI: 10.1002/rmv.2403.

References

Chan L, Hansra G, Robinson P, Graham M . Differential phosphorylation of dynamin I isoforms in subcellular compartments demonstrates the hidden complexity of phosphoproteomes. J Proteome Res. 2010; 9(8):4028-37. DOI: 10.1021/pr100223n. View

Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirchhausen T . Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell. 2006; 10(6):839-50. DOI: 10.1016/j.devcel.2006.04.002. View

McMahon H, Boucrot E . Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol. 2011; 12(8):517-33. DOI: 10.1038/nrm3151. View

Odell L, Howan D, Gordon C, Robertson M, Chau N, Mariana A . The pthaladyns: GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening. J Med Chem. 2010; 53(14):5267-80. DOI: 10.1021/jm100442u. View

van der Bliek A, Meyerowitz E . Dynamin-like protein encoded by the Drosophila shibire gene associated with vesicular traffic. Nature. 1991; 351(6325):411-4. DOI: 10.1038/351411a0. View

Hill T, Mariana A, Gordon C, Odell L, Robertson M, McGeachie A . Iminochromene inhibitors of dynamins I and II GTPase activity and endocytosis. J Med Chem. 2010; 53(10):4094-102. DOI: 10.1021/jm100119c. View

Alexander C, Votruba M, Pesch U, Thiselton D, Mayer S, Moore A . OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000; 26(2):211-5. DOI: 10.1038/79944. View

Robinson P, Sontag J, Liu J, Fykse E, Slaughter C, McMahon H . Dynamin GTPase regulated by protein kinase C phosphorylation in nerve terminals. Nature. 1993; 365(6442):163-6. DOI: 10.1038/365163a0. View

Aridor M, Hannan L . Traffic jam: a compendium of human diseases that affect intracellular transport processes. Traffic. 2001; 1(11):836-51. DOI: 10.1034/j.1600-0854.2000.011104.x. View

10.

Chen M, Obar R, Schroeder C, Austin T, Poodry C, Wadsworth S . Multiple forms of dynamin are encoded by shibire, a Drosophila gene involved in endocytosis. Nature. 1991; 351(6327):583-6. DOI: 10.1038/351583a0. View

11.

Cousin M, Tan T, Robinson P . Protein phosphorylation is required for endocytosis in nerve terminals: potential role for the dephosphins dynamin I and synaptojanin, but not AP180 or amphiphysin. J Neurochem. 2001; 76(1):105-16. DOI: 10.1046/j.1471-4159.2001.00049.x. View

12.

Zuchner S, Noureddine M, Kennerson M, Verhoeven K, Claeys K, De Jonghe P . Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat Genet. 2005; 37(3):289-94. DOI: 10.1038/ng1514. View

13.

Otomo M, Takahashi K, Miyoshi H, Osada K, Nakashima H, Yamaguchi N . Some selective serotonin reuptake inhibitors inhibit dynamin I guanosine triphosphatase (GTPase). Biol Pharm Bull. 2008; 31(8):1489-95. DOI: 10.1248/bpb.31.1489. View

14.

Hinshaw J . Dynamin and its role in membrane fission. Annu Rev Cell Dev Biol. 2000; 16:483-519. PMC: 4781412. DOI: 10.1146/annurev.cellbio.16.1.483. View

15.

Delettre C, Lenaers G, Pelloquin L, Belenguer P, Hamel C . OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. Mol Genet Metab. 2002; 75(2):97-107. DOI: 10.1006/mgme.2001.3278. View

16.

Tomasic T, Masic L . Rhodanine as a privileged scaffold in drug discovery. Curr Med Chem. 2009; 16(13):1596-629. DOI: 10.2174/092986709788186200. View

17.

Noda Y, Nakata T, Hirokawa N . Localization of dynamin: widespread distribution in mature neurons and association with membranous organelles. Neuroscience. 1993; 55(1):113-27. DOI: 10.1016/0306-4522(93)90459-s. View

18.

Bitoun M, Maugenre S, Jeannet P, Lacene E, Ferrer X, Laforet P . Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet. 2005; 37(11):1207-9. DOI: 10.1038/ng1657. View

19.

Krueger B, Forn J, Greengard P . Depolarization-induced phosphorylation of specific proteins, mediated by calcium ion influx, in rat brain synaptosomes. J Biol Chem. 1977; 252(8):2764-73. View

20.

Welsch M, Snyder S, Stockwell B . Privileged scaffolds for library design and drug discovery. Curr Opin Chem Biol. 2010; 14(3):347-61. PMC: 2908274. DOI: 10.1016/j.cbpa.2010.02.018. View