Trends in Neosubstrate Degradation by Cereblon-Based Molecular Glues and the Development of Novel Multiparameter Optimization Scores.
J Med Chem
; 67(2): 1327-1335, 2024 Jan 25.
Article
en En
| MEDLINE
| ID: mdl-38170610
ABSTRACT
Molecular glues enable the degradation of previously "undruggable" proteins via the recruitment of cereblon (CRBN) to the target. One major challenge in designing CRBN E3 ligase modulating compounds (CELMoDs) is the selectivity profile toward neosubstrates, proteins recruited by CRBN E3 ligase agents for degradation. Common neosubstrates include Aiolos, Ikaros, GSPT1, CK1α, and SALL4. Unlike achieving potency and selectivity for traditional small molecule inhibitors, reducing the degradation of these neosubstrates is complicated by the ternary nature of the complex formed between the protein, CRBN, and CELMoD. The standard guiding principles of medicinal chemistry, such as enforcing hydrogen bond formation, are less predictive of degradation efficiency and selectivity. Disclosed is an analysis of our glutarimide CELMoD library to identify interpretable chemical features correlated to selectivity profiles and general cytotoxicity. Included is a simple multiparameter optimization function using only three parameters to predict whether molecules will have undesired neosubstrate activity.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ubiquitina-Proteína Ligasas
/
Proteínas Adaptadoras Transductoras de Señales
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos