Pyrimidyn compounds: Dual-action small molecule pyrimidine-based dynamin inhibitors

Andrew McGeachie, Luke Odell, Annie Quan, James Daniel, Ngoc Chau, Timothy Hill, Damien Keating, Michael Cousin, Ellen van Dam, Anna Mariana, Ainslie Whiting, Swetha Perera, Aimee Novelle, Kelly Young, Fiona Deane, Jayne Gilbert, Jennette Sakoff, Megan Chircop, Adam McCluskey, Phillip Robinson

    Research output: Contribution to journalArticlepeer-review

    15 Citations (Scopus)

    Abstract

    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 IC 50 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.

    Original languageEnglish
    Pages (from-to)1507-1518
    Number of pages12
    JournalACS Chemical Biology
    Volume8
    Issue number7
    DOIs
    Publication statusPublished - 19 Jul 2013

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