Ispinesib as an Effective Warhead for the Design of Autophagosome-Tethering Chimeras: Discovery of Potent Degraders of Nicotinamide Phosphoribosyltransferase (NAMPT).
J Med Chem
; 65(11): 7619-7628, 2022 06 09.
Article
en En
| MEDLINE
| ID: mdl-35588495
Autophagosome-tethering compounds (ATTECs) are an emerging new technology in targeted protein degradation. However, effective tools and successful examples for autophagosome-tethering chimeras are still rather limited. Herein, ATTEC ispinesib was identified for the first time to be an effective warhead to design autophagosome-tethering chimeras. As a conceptual validation study, the first generation of autophagic degraders of nicotinamide phosphoribosyltransferase (NAMPT) were developed by connecting the NAMPT inhibitor and LC3-binding ispinesib through a flexible linker. In particular, compound A3 significantly induced the degradation of NAMPT through the autophagy-lysosomal pathway, leading to excellent cellular antitumor potency. Ispinesib may have broad applications in the design of potent autophagosome-tethering chimeras.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Nicotinamida Fosforribosiltransferasa
/
Autofagosomas
Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2022
Tipo del documento:
Article