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Bioorg Med Chem Lett. 2010 Aug 15;20(16):4858-64. doi: 10.1016/j.bmcl.2010.06.092. Epub 2010 Jun 22.

Synthesis of potent chemical inhibitors of dynamin GTPase.

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Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea.


Dynamin is a key regulatory protein in clathrin mediated endocytosis. Compared to genetic or immunological tools, small chemical dynamin inhibitors such as dynasore have the potential to study the dynamic nature of endocytic events in cells. Dynasore inhibits dynamin GTPase activity and transferrin uptake at IC(50) approximately 15 microM but use in some biological applications requires more potent inhibitor than dynasore. Here, we chemically modified the side chains of dynasore and found that two derivatives, DD-6 and DD-11 more potently inhibited transferrin uptake (IC(50): 4.00 microM for DD-6, 2.63 microM for DD-11) and dynamin GTPase activity (IC(50): 5.1 microM for DD-6, 3.6 microM for DD-11) than dynasore. The effect was reversible and they were washed more rapidly out than dynasore. TIRF microscopy showed that they stabilize the clathrin coats on the membrane. Our results indicated that new dynasore derivatives are more potent inhibitor of dynamin, displaying promise as leads for the development of more effective analogues for broader biological applications.

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