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.
http://pubs.acs.org/doi/abs/10.1021/ml200284s
Dynamin is required for clathrin-mediated endocytosis (CME).
Its GTPase activity is stimulated by phospholipid binding to its PH domain, which induces helical oligomerization.
We have designed a series of novel pyrimidine-based “Pyrimidyn” compounds that inhibit the lipid-stimulated GTPase activity of full length dynamin I and II with similar potency.
The most potent analogue, Pyrimidyn 7, has an IC50 of 1.1 μM for
dynamin I and 1.8 μM for dynamin II, making it among the most potent dynamin inhibitors identified to date.
We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin.
The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby to target two distinct domains of dynamin.
Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals.
Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation.
This dual mode of action provides an important new tool for molecular dissection of dynamin’s role in endocytosis.
We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin.
The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby to target two distinct domains of dynamin.
Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals.
Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation.
This dual mode of action provides an important new tool for molecular dissection of dynamin’s role in endocytosis.
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