9htl

Publication Abstract from PubMed

In this work we present an easy, one-step synthetic protocol to explore a large chemical space of glutarimide-based cereblon (CRBN) ligands for targeted protein degradation. It is built upon our recently suggested approach to generating structurally diverse series of alpha-substituted glutarimide derivatives through an efficient Rh(II)-catalyzed X-H insertion reaction of 3-diazopiperidine-2,6-dione, with moderate to high yields. In total, 25 glutarimide derivatives incorporating variable side chains were synthesized and evaluated in vitro. All ligands showed a favorable lipophilicity, and several were able to outperform the binding affinity of thalidomide as a reference. In addition, most compounds showed low intrinsic cytotoxicity in myeloma cell lines and human peripheral blood mononuclear cells, and did not recruit canonical neosubstrates. A cellular thermal shift assay further demonstrated that the most potent analogs stabilize CRBN in live cells, confirming their on-target engagement. The development of the series was accompanied by a crystallographic study, which rationalizes the observed improvements in binding affinity and neosubstrate selectivity, and can support further development towards molecular glue activity and PROTACs design.

Extending the chemical space of glutarimide-based cereblon ligands through an efficient Rh(II)-catalyzed X-H insertion reaction.,Levashova E, Bischof L, Bunev A, Sapegin A, Grygor'eva O, Kudinov A, Ebeling S, Tatarinov I, Dar'in D, Kantin G, Hartmann MD, Kalinin S Eur J Med Chem. 2025 Oct 3;301:118235. doi: 10.1016/j.ejmech.2025.118235. PMID:41086529^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.