Fragment-based discovery of a novel, brain penetrant, orally active HDAC2 inhibitor

DOI: 10.1021/acsmedchemlett.2c00272

Authors: Emiliano Tamanini (Astex Pharmaceuticals) , Shin Miyamura (Otsuka Pharmaceutical Co., Ltd) , Ildiko M. Buck (Astex Pharmaceuticals) , Benjamin D. Cons (Astex Pharmaceuticals) , Lee Dawson (Astex Pharmaceuticals) , Charlotte East (Astex Pharmaceuticals) , Takashi Futamura (Otsuka Pharmaceutical Co., Ltd) , Shintaro Goto (Otsuka Pharmaceutical Co., Ltd) , Charlotte Griffiths-Jones (Astex Pharmaceuticals) , Tetsuya Hashimoto (Otsuka Pharmaceutical Co., Ltd.) , Tom D. Heightman (Astex Pharmaceuticals) , Shunpei Ishikawa , Hideki Ito (Otsuka Pharmaceutical Co., Ltd.) , Yosuke Kaneko (Otsuka Pharmaceutical Co., Ltd.) , Tatsuya Kawato (Otsuka Pharmaceutical Co., Ltd.) , Kazumi Kondo (Otsuka Pharmaceutical Co., Ltd.) , Naoki Kurihara (Otsuka Pharmaceutical Co., Ltd.) , James M. Mccarthy (Astex Pharmaceuticals) , Yukiko Mori (Otsuka Pharmaceutical Co., Ltd.) , Tsuyoshi Nagase (Otsuka Pharmaceutical Co., Ltd.) , Yuichiro Nakaishi (Otsuka Pharmaceutical Co., Ltd.) , Judith Reeks (Astex Pharmaceuticals) , Akimasa Sato (Otsuka Pharmaceutical Co., Ltd.) , Patrick Schöpf (Astex Pharmaceuticals) , Kuninori Tai (Otsuka Pharmaceutical Co., Ltd.) , Taichi Tamai (Otsuka Pharmaceutical Co., Ltd.) , Dominic Tisi (Astex Pharmaceuticals) , Alison J.-A. Woolford (Astex Pharmaceuticals)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: September 2022

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.

Journal Keywords: Histone deacetylase; fragment-based drug discovery; structure-based optimization; CNS

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ID23-1 at ESRF

Added On: 27/09/2022 09:54

Discipline Tags:

Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)