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SUMMARY STATEMENT 41A gain-of-function screen of the human kinome revealed AAK1 as a negative regulator of WNT 42 signaling. We show that AAK1 promotes clathrin-mediated endocytosis of LRP6, resulting in 43 downregulation of WNT signaling. We use a new selective and potent AAK1/BMP2K small 44 molecule probe to validate our findings.
Understanding the structural determinants of inhibitor selectivity would 18 facilitate the design and preparation of kinase probes. We describe a pair of matched 19 compounds differing only by one degree of saturation but showing dramatic differential 20 activities at select kinases. We utilized x-ray crystallography and computational analysis 21 to rationalize the basis of the differential activity. 22
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