Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.
Basic Information
ID: ALA5113540
Journal: ACS Med Chem Lett
Title: Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.
Authors: Tamanini E, Miyamura S, Buck IM, Cons BD, Dawson L, East C, Futamura T, Goto S, Griffiths-Jones C, Hashimoto T, Heightman TD, Ishikawa S, Ito H, Kaneko Y, Kawato T, Kondo K, Kurihara N, McCarthy JM, Mori Y, Nagase T, Nakaishi Y, Reeks J, Sato A, Schöpf P, Tai K, Tamai T, Tisi D, Woolford AJ.
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.
CiteXplore: 36262388
DOI: 10.1021/acsmedchemlett.2c00272
Patent ID: ┄