Dataset Information

Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.

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.

SUBMITTER: Tamanini E

PROVIDER: S-EPMC9575179 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.

Tamanini Emiliano E Miyamura Shin S Buck Ildiko M IM Cons Benjamin D BD Dawson Lee L East Charlotte C Futamura Takashi T Goto Shintaro S Griffiths-Jones Charlotte C Hashimoto Tetsuya T Heightman Tom D TD Ishikawa Shunpei S Ito Hideki H Kaneko Yosuke Y Kawato Tatsuya T Kondo Kazumi K Kurihara Naoki N McCarthy James M JM Mori Yukiko Y Nagase Tsuyoshi T Nakaishi Yuichiro Y Reeks Judith J Sato Akimasa A Schöpf Patrick P Tai Kuninori K Tamai Taichi T Tisi Dominic D Woolford Alison J-A AJ

ACS medicinal chemistry letters 20220906 10

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, ...[more]

PMID: 36262388

Dataset Information

Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.

Publications

Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.

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