Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor
Emiliano Tamanini, Shin Miyamura, Ildiko M. Buck, Benjamin D. Cons, Lee A. Dawson, Charlotte East, Takashi Futamura, Shintaro Goto, Charlotte Griffiths-Jones, Tetsuya Hashimoto, Tom D. Heightman, Shunpei Ishikawa, Hideki Ito, Yosuke Kaneko, Tatsuya Kawato, Kazumi Kondo, Naoki Kurihara, J. Michael McCarthy, Yukiko Mori, Tsuyoshi Nagase, Yuichiro Nakaishi, Judith Reeks, Akimasa Sato, Patrick Schöpf, Kuninori Tai, Taichi Tamai, Dominic Tisi, Alison J.‐A. Woolford
Abstract
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.