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Library 1 was based on Pitstop 2, but no notable clathrin PPI or in\u2010cell activity was observed. With the Pitstop 1, 16 analogues were produced with 1,8\u2010naphthalic imide core as a foundation. Analogues with methylene spaced linkers and simple amides showed a modest to good range of PPI inhibition (7.6\u201342.5\u2005\u03bcM, naphthyl <jats:bold>39<\/jats:bold> and 4\u2010nitrophenyl <jats:bold>40<\/jats:bold> respectively) activity. These data reveal the importance of the naphthalene sulfonate moiety, with no des\u2010SO<jats:sub>3<\/jats:sub> analogue displaying PPI inhibition. This was consistent with the observed analogue docked poses within the clathrin terminal domain Site 1 binding pocket. Further modifications targeted the naphthalene imide moiety, with the installation of 5\u2010Br (<jats:bold>45\u2009a<\/jats:bold>), 5\u2010OH (<jats:bold>45\u2009c<\/jats:bold>) and 5\u2010propyl ether (<jats:bold>45\u2009d<\/jats:bold>) moieties. Among them, the OH <jats:bold>45\u2009c<\/jats:bold> and propyl ether <jats:bold>45\u2009d<\/jats:bold> retained PPI inhibition, with propyl ether <jats:bold>45\u2009d<\/jats:bold> being the most active with a PPI inhibition IC<jats:sub>50<\/jats:sub>=7.3\u2005\u03bcM. This is 2x more potent than Pitstop 2 and 3x more potent than Pitstop 1.<\/jats:p>","DOI":"10.1002\/cmdc.202400253","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T02:06:31Z","timestamp":1718762791000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Inhibition Clathrin Mediated Endocytosis: Pitstop 1\u2009and Pitstop 2 Chimeras"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0458-5037","authenticated-orcid":false,"given":"Kate","family":"Prichard","sequence":"first","affiliation":[{"name":"Chemistry School of Environmental &amp; Life Sciences The University of Newcastle  University Drive Callaghan, NSW 2308 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5507-0493","authenticated-orcid":false,"given":"Ngoc","family":"Chau","sequence":"additional","affiliation":[{"name":"Cell Signalling Unit Children's Medical Research Institute The University of Sydney  Hawkesbury Road Westmead, Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1062-2881","authenticated-orcid":false,"given":"Jing","family":"Xue","sequence":"additional","affiliation":[{"name":"Cell Signalling Unit Children's Medical Research Institute The University of Sydney  Hawkesbury Road Westmead, Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1010-9723","authenticated-orcid":false,"given":"Michael","family":"Krauss","sequence":"additional","affiliation":[{"name":"Leibniz Institute fur Molecular Pharmacologie Department of Biology, Chemistry, Pharmacy  Robert-Roessle-Strasse 10 Berlin 13125 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennette A.","family":"Sakoff","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics Group Medical Oncology Calvary Mater Newcastle Hospital  Edith Street Waratah, NSW 2298 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5034-386X","authenticated-orcid":false,"given":"Jayne","family":"Gilbert","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics Group Medical Oncology Calvary Mater Newcastle Hospital  Edith Street Waratah, NSW 2298 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Bahnik","sequence":"additional","affiliation":[{"name":"Leibniz Institute fur Molecular Pharmacologie Department of Biology, Chemistry, Pharmacy  Robert-Roessle-Strasse 10 Berlin 13125 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0284-0425","authenticated-orcid":false,"given":"Maria","family":"Muehlbauer","sequence":"additional","affiliation":[{"name":"Leibniz Institute fur Molecular Pharmacologie Department of Biology, Chemistry, Pharmacy  Robert-Roessle-Strasse 10 Berlin 13125 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2688-2868","authenticated-orcid":false,"given":"Silke","family":"Radetzki","sequence":"additional","affiliation":[{"name":"Leibniz Institute fur Molecular Pharmacologie Department of Biology, Chemistry, Pharmacy  Robert-Roessle-Strasse 10 Berlin 13125 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7878-0313","authenticated-orcid":false,"given":"Phillip J.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Cell Signalling Unit Children's Medical Research Institute The University of Sydney  Hawkesbury Road Westmead, Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3119-6993","authenticated-orcid":false,"given":"Volker","family":"Haucke","sequence":"additional","affiliation":[{"name":"Leibniz Institute fur Molecular Pharmacologie Department of Biology, Chemistry, Pharmacy  Robert-Roessle-Strasse 10 Berlin 13125 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7125-863X","authenticated-orcid":false,"given":"Adam","family":"McCluskey","sequence":"additional","affiliation":[{"name":"Chemistry School of Environmental &amp; 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