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PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein\u2013stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine X\u2010ray crystallographic data from both stabilizer and inhibitor co\u2010crystal complexes of the adapter protein 14\u20103\u20103 to characterize, down to the atomic scale, inhibitors of the 14\u20103\u20103\/Tau PPI, a potential drug target to treat Alzheimer\u2019s disease. The most potent compound notably inhibited the binding of phosphorylated full\u2010length Tau to 14\u20103\u20103 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer\u2013protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14\u20103\u20103 and other PPIs.<\/jats:p>","DOI":"10.1002\/anie.201507976","type":"journal-article","created":{"date-parts":[[2015,11,5]],"date-time":"2015-11-05T12:47:03Z","timestamp":1446727623000},"page":"15720-15724","source":"Crossref","is-referenced-by-count":66,"title":["Stabilizer\u2010Guided Inhibition of Protein\u2013Protein Interactions"],"prefix":"10.1002","volume":"54","author":[{"given":"Lech\u2010Gustav","family":"Milroy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Bartel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morkos A.","family":"Henen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppe","family":"Leysen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joris M. 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