81316-56-5Relevant articles and documents
Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods
Kessler, Dirk,Mayer, Moriz,Zahn, Stephan K.,Zeeb, Markus,W?hrle, Simon,Bergner, Andreas,Bruchhaus, Jens,Ciftci, Tuncay,Dahmann, Georg,Dettling, Maike,D?bel, Sandra,Fuchs, Julian E.,Geist, Leonhard,Hela, Wolfgang,Kofink, Christiane,Kousek, Roland,Moser, Franziska,Puchner, Teresa,Rumpel, Klaus,Scharnweber, Maximilian,Werni, Patrick,Wolkerstorfer, Bernhard,Breitsprecher, Dennis,Baaske, Philipp,Pearson, Mark,McConnell, Darryl B.,B?ttcher, Jark
, p. 1420 - 1424 (2021)
Aberrant WNT pathway activation, leading to nuclear accumulation of β-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β-catenin and subsequent nuclear translocation. Restoring cellular degradation of β-catenin represents a potential therapeutic strategy. Here, we report the fragment-based discovery of a small molecule binder to β-catenin, including the structural elucidation of the binding mode by X-ray crystallography. The difficulty in drugging β-catenin was confirmed as the primary screening campaigns identified only few and very weak hits. Iterative virtual and NMR screening techniques were required to discover a compound with sufficient potency to be able to obtain an X-ray co-crystal structure. The binding site is located between armadillo repeats two and three, adjacent to the BCL9 and TCF4 binding sites. Genetic studies show that it is unlikely to be useful for the development of protein–protein interaction inhibitors but structural information and established assays provide a solid basis for a prospective optimization towards β-catenin proteolysis targeting chimeras (PROTACs) as alternative modality.
Highly regioselective ring-opening of epoxides with amines: A metal- A nd solvent-free protocol for the synthesis of β-amino alcohols
Li, Dong,Wang, Jing,Yu, Shibo,Ye, Silei,Zou, Wenjie,Zhang, Hongbin,Chen, Jingbo
supporting information, p. 2256 - 2259 (2020/03/04)
We herein report a metal- A nd solvent-free acetic acid-mediated ring-opening reaction of epoxides with amines. This process provides β-amino alcohols in high yields with excellent regioselectivity. Importantly, this epoxide ring-opening protocol can be used for the introduction of amines in natural products during late-stage transformations.
A Dieckmann cyclization route to piperazine-2,5-diones
Aboussafy, Claude Larrivee,Clive, Derrick L. J.
supporting information; experimental part, p. 5125 - 5131 (2012/07/03)
Piperazine-2,5-diones are formed by Dieckmann cyclization (NaH, THF) of substructures of the type CH2-N(R)C(O)CH2N(R′) CO2Ph in which the terminal methylene (CH2) that is adjacent to nitrogen closes onto the carbonyl group of the phenyl carbamate unit at the other end of the chain. R and R′ are alkyl groups, and the terminal methylene is activated by a ketone carbonyl, a nitrile, an ester, or a phosphoryl group. The starting materials are assembled by standard acylation and oxidation processes, starting from a β-(alkylamino)alcohol, an (alkylamino)acetonitrile, an (alkylamino) ester, or an (alkylamino)methyl phosphonate.
