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

Hill, Timothy A., Gordon, Christopher P., McGeachie, Andrew B., Venn-Brown, Barbara, Odell, Luke R., Chau, Ngoc, Quan, Annie, Mariana, Anna, Sakoff, Jennette A., Chircop (nee Fabbro), Megan, Robinson, Phillip J. and McCluskey, Adam (2009) Inhibition of dynamin mediated endocytosis by the Dynoles - synthesis and functional activity of a family of indoles. Journal of Medicinal Chemistry, 52 12: 3762-3773. doi:10.1021/jm900036m


Author Hill, Timothy A.
Gordon, Christopher P.
McGeachie, Andrew B.
Venn-Brown, Barbara
Odell, Luke R.
Chau, Ngoc
Quan, Annie
Mariana, Anna
Sakoff, Jennette A.
Chircop (nee Fabbro), Megan
Robinson, Phillip J.
McCluskey, Adam
Title Inhibition of dynamin mediated endocytosis by the Dynoles - synthesis and functional activity of a family of indoles
Formatted title
Inhibition of dynamin mediated endocytosis by the Dynoles - synthesis and functional activity of a family of indoles
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2009-06-25
Sub-type Article (original research)
DOI 10.1021/jm900036m
Open Access Status Not yet assessed
Volume 52
Issue 12
Start page 3762
End page 3773
Total pages 12
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
Screening identified two bisindolylmaleimides as 100 μM 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 μM 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 (IC50 ∼15 μM; RME IC50 ∼80 μM). The dynoles represent a new series of tools to better probe endocytosis and dynamin-mediated trafficking events in a variety of cells.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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