84767-67-9Relevant articles and documents
De-novo design of cereblon (CRBN) effectors guided by natural hydrolysis products of thalidomide derivatives
Heim, Christopher,Pliatsika, Dimanthi,Mousavizadeh, Farnoush,B?r, Kerstin,Hernandez Alvarez, Birte,Giannis, Athanassios,Hartmann, Marcus D.
, p. 6615 - 6629 (2019/08/20)
Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.
Synthesis and evaluation of anti-apoptotic activity of L-carnitine cyclic analogues and amino acid derivatives
Fringuelli, Renata,Utrilla Navarro, M. Pilar,Milanese, Lara,Bruscoli, Stefano,Schiaffella, Fausto,Riccardi, Carlo,De Simone, Claudio
, p. 271 - 277 (2007/10/03)
Two series of derivatives were synthesised. In one series (R)-4-hydroxy-2-pyrrolidinone was used as a mimic of cyclic L-carnitine analogue and in the second series 3-amino-2-piperidinone was used as a cyclic ornithine analogue. N-Benzyloxycarbonyl derivatives of some amino acids were also prepared. The newly synthesised compounds were tested for their ability to inhibit Fas-activated apoptosis of human Jurkatt T-cell line. The results confirm the previously described anti-apoptotic activity of carnitine and indicate new carnitine and amino acid analogues (1, 3, 6, 7, 20) that inhibit Fas-induced apoptosis.
