Synthesis of potent chemical inhibitors of dynamin GTPase

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 IC50 ∼15 μM 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 (IC50: 4.00 μM for DD-6, 2.63 μM for DD-11) and dynamin GTPase activity (IC50: 5.1 μM for DD-6, 3.6 μM 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.

The synthesis of the potent dynamin GTPase inhibitors (IC50 = 5.1 μM for DD-6; 3.6 μM for DD-11) is reported.Figure optionsDownload as PowerPoint slide