Selective and Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors That Reduce α-Synuclein Phosphorylation in Rat Brain (pages 1295–1313)
Dr. Danielle L. Aubele, Dr. Roy K. Hom, Dr. Marc Adler, Dr. Robert A. Galemmo Jr., Dr. Simeon Bowers, Dr. Anh P. Truong, Dr. Hu Pan, Dr. Paul Beroza, Dr. R. Jeffrey Neitz, Dr. Nanhua Yao, May Lin, Dr. George Tonn, Heather Zhang, Dr. Michael P. Bova, Dr. Zhao Ren, Danny Tam, Lany Ruslim, Dr. Jeanne Baker, Linnea Diep, Dr. Kent Fitzgerald, Jennifer Hoffman, Ruth Motter, Donald Fauss, Pearl Tanaka, Dr. Michael Dappen, Dr. Jacek Jagodzinski, Wayman Chan, Dr. Andrei W. Konradi, Dr. Lee Latimer, Dr. Yong L. Zhu, Dr. Hing L. Sham, Dr. John P. Anderson, Dr. Marcelle Bergeron and Dr. Dean R. Artis
Version of Record online: 21 JUN 2013 | DOI: 10.1002/cmdc.201300166
Gets into your head: By using a structure-guided drug discovery approach, highly selective brain-penetrant Plk-2 inhibitors were designed with the use of an interesting aromatic edge–face interaction as a potency–selectivity determinant. An analogue from this work lowered phosphorylated α-synuclein levels in vivo on oral dosing, demonstrating successful target engagement in the rat brain and paving the way for proof-of-concept studies in rodent models of Parkinson's disease.