Inhibition of dynamin mediated endocytosis by the dynoles--synthesis and functional activity of a family of indoles - PubMed (original) (raw)

. 2009 Jun 25;52(12):3762-73.

doi: 10.1021/jm900036m.

Christopher P Gordon, Andrew B McGeachie, Barbara Venn-Brown, Luke R Odell, Ngoc Chau, Annie Quan, Anna Mariana, Jennette A Sakoff, Megan Chircop, Phillip J Robinson, Adam McCluskey

Affiliations

• PMID: 19459681
• DOI: 10.1021/jm900036m

Inhibition of dynamin mediated endocytosis by the dynoles--synthesis and functional activity of a family of indoles

Timothy A Hill et al. J Med Chem. 2009.

Abstract

Screening identified two bisindolylmaleimides as 100 microM inhibitors of the GTPase activity of dynamin I. Focused library approaches allowed development of indole-based dynamin inhibitors called dynoles. 100-Fold in vitro enhancement of potency was noted with the best inhibitor, 2-cyano-3-(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-N-octylacrylamide (dynole 34-2), a 1.3 +/- 0.3 microM dynamin I inhibitor. Dynole 34-2 potently inhibited receptor mediated endocytosis (RME) internalization of Texas red-transferrin. The rank order of potency for a variety of dynole analogues on RME in U2OS cells matched their rank order for dynamin inhibition, suggesting that the mechanism of inhibition is via dynamin. Dynoles are the most active dynamin I inhibitors reported for in vitro or RME evaluations. Dynole 34-2 is 15-fold more active than dynasore against dynamin I and 6-fold more active against dynamin mediated RME (IC(50) approximately 15 microM; RME IC(50) approximately 80 microM). The dynoles represent a new series of tools to better probe endocytosis and dynamin-mediated trafficking events in a variety of cells.

PubMed Disclaimer

Similar articles

• Development of second-generation indole-based dynamin GTPase inhibitors.
  Gordon CP, Venn-Brown B, Robertson MJ, Young KA, Chau N, Mariana A, Whiting A, Chircop M, Robinson PJ, McCluskey A. Gordon CP, et al. J Med Chem. 2013 Jan 10;56(1):46-59. doi: 10.1021/jm300844m. Epub 2012 Dec 18. J Med Chem. 2013. PMID: 23167654
• Myristyl trimethyl ammonium bromide and octadecyl trimethyl ammonium bromide are surface-active small molecule dynamin inhibitors that block endocytosis mediated by dynamin I or dynamin II.
  Quan A, McGeachie AB, Keating DJ, van Dam EM, Rusak J, Chau N, Malladi CS, Chen C, McCluskey A, Cousin MA, Robinson PJ. Quan A, et al. Mol Pharmacol. 2007 Dec;72(6):1425-39. doi: 10.1124/mol.107.034207. Epub 2007 Aug 16. Mol Pharmacol. 2007. PMID: 17702890
• Iminochromene inhibitors of dynamins I and II GTPase activity and endocytosis.
  Hill TA, Mariana A, Gordon CP, Odell LR, Robertson MJ, McGeachie AB, Chau N, Daniel JA, Gorgani NN, Robinson PJ, McCluskey A. Hill TA, et al. J Med Chem. 2010 May 27;53(10):4094-102. doi: 10.1021/jm100119c. J Med Chem. 2010. PMID: 20426422
• Targeting membrane trafficking in infection prophylaxis: dynamin inhibitors.
  Harper CB, Popoff MR, McCluskey A, Robinson PJ, Meunier FA. Harper CB, et al. Trends Cell Biol. 2013 Feb;23(2):90-101. doi: 10.1016/j.tcb.2012.10.007. Epub 2012 Nov 17. Trends Cell Biol. 2013. PMID: 23164733 Review.
• Discovery and combinatorial synthesis of fungal metabolites beauveriolides, novel antiatherosclerotic agents.
  Tomoda H, Doi T. Tomoda H, et al. Acc Chem Res. 2008 Jan;41(1):32-9. doi: 10.1021/ar700117b. Epub 2007 Sep 6. Acc Chem Res. 2008. PMID: 17803269 Review.

Cited by

• Identification of drug-like molecules targeting the ATPase activity of dynamin-like EHD4.
  Mohd S, Oder A, Specker E, Neuenschwander M, Von Kries JP, Daumke O. Mohd S, et al. PLoS One. 2024 Jul 29;19(7):e0302704. doi: 10.1371/journal.pone.0302704. eCollection 2024. PLoS One. 2024. PMID: 39074100 Free PMC article.
• JC Polyomavirus Entry by Clathrin-Mediated Endocytosis Is Driven by β-Arrestin.
  Mayberry CL, Soucy AN, Lajoie CR, DuShane JK, Maginnis MS. Mayberry CL, et al. J Virol. 2019 Apr 3;93(8):e01948-18. doi: 10.1128/JVI.01948-18. Print 2019 Apr 15. J Virol. 2019. PMID: 30700597 Free PMC article.
• Cellular uptake and intracellular trafficking of oligonucleotides.
  Juliano RL, Carver K. Juliano RL, et al. Adv Drug Deliv Rev. 2015 Jun 29;87:35-45. doi: 10.1016/j.addr.2015.04.005. Epub 2015 Apr 14. Adv Drug Deliv Rev. 2015. PMID: 25881722 Free PMC article. Review.
• Simultaneous stabilization of actin cytoskeleton in multiple nephron-specific cells protects the kidney from diverse injury.
  Mukherjee K, Gu C, Collins A, Mettlen M, Samelko B, Altintas MM, Sudhini YR, Wang X, Bouley R, Brown D, Pedro BP, Bane SL, Gupta V, Brinkkoetter PT, Hagmann H, Reiser J, Sever S. Mukherjee K, et al. Nat Commun. 2022 May 3;13(1):2422. doi: 10.1038/s41467-022-30101-4. Nat Commun. 2022. PMID: 35504916 Free PMC article.
• Inhibition of endocytosis suppresses the nitric oxide-dependent release of Cl- in retinal amacrine cells.
  Dunn VK, Gleason E. Dunn VK, et al. PLoS One. 2018 Jul 25;13(7):e0201184. doi: 10.1371/journal.pone.0201184. eCollection 2018. PLoS One. 2018. PMID: 30044876 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • American Chemical Society

• Other Literature Sources

  • The Lens - Patent Citations Database

• Chemical Information

  • BindingDB