116315-07-2Relevant academic research and scientific papers
A Multifaceted Hit-Finding Approach Reveals Novel LC3 Family Ligands
Bruning, John M.,Burdick, Daniel J.,Cai, Jianping,Crawford, Terry,Decurtins, Willy,Dueber, Erin C.,Fang, Chunlin,Grubers, Felix,Helgason, Elizabeth,Holliday, Michael J.,Langley, Allyson,Li, Ke Sherry,Mulvihill, Melinda M.,Petersen, Ann,Popovych, Nataliya,Rougé, Lionel,Satz, Alexander Lee,Skelton, Nicholas,Song, Aimin,Staben, Steven T.,Steffek, Micah,Stoffler, Daniel,Strebel, Quentin,Tom, Jeffrey Y. K.,Wichert, Moreno,Xue, Jing
, (2022/01/19)
Autophagy-related proteins (Atgs) drive the lysosome-mediated degradation pathway, autophagy, to enable the clearance of dysfunctional cellular components and maintain homeostasis. In humans, this process is driven by the mammalian Atg8 (mAtg8) family of proteins comprising the LC3 and GABARAP subfamilies. The mAtg8 proteins play essential roles in the formation and maturation of autophagosomes and the capture of specific cargo through binding to the conserved LC3-interacting region (LIR) sequence within target proteins. Modulation of interactions of mAtg8 with its target proteins via small-molecule ligands would enable further interrogation of their function. Here we describe unbiased fragment and DNA-encoded library (DEL) screening approaches for discovering LC3 small-molecule ligands. Both strategies resulted in compounds that bind to LC3, with the fragment hits favoring a conserved hydrophobic pocket in mATG8 proteins, as detailed by LC3A-fragment complex crystal structures. Our findings demonstrate that the malleable LIR-binding surface can be readily targeted by fragments; however, rational design of additional interactions to drive increased affinity proved challenging. DEL libraries, which combine small, fragment-like building blocks into larger scaffolds, yielded higher-affinity binders and revealed an unexpected potential for reversible, covalent ligands. Moreover, DEL hits identified possible vectors for synthesizing fluorescent probes or bivalent molecules for engineering autophagic degradation of specific targets.
Catechol derivatives
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, (2008/06/13)
Catechol derivatives of the formula STR1 wherein Ra, Rb and Rc have the significance given herein, the ester and ether derivatives thereof which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof are described and possess valuable pharmacological properties. In particular, they inhibit the enzyme catechol-O-methyltransferase (COMT), a soluble, magnesium-dependent enzyme which catalyses the transference of the methyl group of S-adensoylmethionine to a catechol substrate, whereby the corresponding methyl ethers are formed. Suitable substrates which can be O-methylated by COMT and which can thus be deactivated are, for example, extraneuornal catecholamines and exogeneously-administered therapeutically active substances having a catechol structure. Formula Ia above embraces not only compounds which form part of the invention, but also known compounds; the compounds which form part of the invention can be prepared according to known methods.
