5537-74-6Relevant articles and documents
Demonstrating Ligandability of the LC3A and LC3B Adapter Interface
Hartmann, Markus,Huber, Jessica,Kramer, Jan S.,Heering, Jan,Pietsch, Larissa,Stark, Holger,Odadzic, Dalibor,Bischoff, Iris,Fürst, Robert,Schr?der, Martin,Akutsu, Masato,Chaikuad, Apirat,D?tsch, Volker,Knapp, Stefan,Biondi, Ricardo M.,Rogov, Vladimir V.,Proschak, Ewgenij
, p. 3720 - 3746 (2021/05/04)
Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).
Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis
Migliore, Marco,Pontis, Silvia,Fuentes de Arriba, Angel Luis,Realini, Natalia,Torrente, Esther,Armirotti, Andrea,Romeo, Elisa,Di Martino, Simona,Russo, Debora,Pizzirani, Daniela,Summa, Maria,Lanfranco, Massimiliano,Ottonello, Giuliana,Busquet, Perrine,Jung, Kwang -Mook,Garcia-Guzman, Miguel,Heim, Roger,Scarpelli, Rita,Piomelli, Daniele
supporting information, p. 11193 - 11197 (2016/10/13)
Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, N-acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti-inflammatory therapy, the lipid-like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole–piperazine derivatives that inhibit NAAA in a potent and selective manner by a non-covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non-covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders.
