Article
作者: Tamanini, Emiliano ; Miyamura, Shin ; Buck, Ildiko M. ; Cons, Benjamin D. ; Dawson, Lee ; East, Charlotte ; Futamura, Takashi ; Goto, Shintaro ; Griffiths-Jones, Charlotte ; Hashimoto, Tetsuya ; Heightman, Tom D. ; Ishikawa, Shunpei ; Ito, Hideki ; Kaneko, Yosuke ; Kawato, Tatsuya ; Kondo, Kazumi ; Kurihara, Naoki ; McCarthy, James M. ; Mori, Yukiko ; Nagase, Tsuyoshi ; Nakaishi, Yuichiro ; Reeks, Judith ; Sato, Akimasa ; Schopf, Patrick ; Tai, Kuninori ; Tamai, Taichi ; Tisi, Dominic ; Woolford, Alison J.-A.
Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein-ligand complex X-ray structures, into a sub-μM, brain penetrant, HDAC2 inhibitor (17) capable of modulating histone acetylation levels in vivo.