Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models.
Arch Pharm (Weinheim)
; 355(5): e2100467, 2022 May.
Article
in English
| MEDLINE | ID: covidwho-1680268
ABSTRACT
Although the androgen receptor (AR) is a validated target for the treatment of prostate cancer, resistance to antiandrogens necessitates the development of new therapeutic modalities. Exploiting the ubiquitin-proteasome system with proteolysis-targeting chimeras (PROTACs) has become a practical approach to degrade specific proteins and thus to extend the portfolio of small molecules used for the treatment of a broader spectrum of diseases. Herein, we present three subgroups of enzalutamide-based PROTACs in which only the exit vector was modified. By recruiting cereblon, we were able to demonstrate the potent degradation of AR in lung cancer cells. Furthermore, the initial evaluation enabled the design of an optimized PROTAC with a rigid linker that degraded AR with a DC50 value in the nanomolar range. These results provide novel AR-directed PROTACs and a clear rationale for further investigating AR involvement in lung cancer models.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Prostatic Neoplasms
/
Receptors, Androgen
/
Lung Neoplasms
Type of study:
Experimental Studies
/
Prognostic study
Limits:
Humans
/
Male
Language:
English
Journal:
Arch Pharm (Weinheim)
Year:
2022
Document Type:
Article
Affiliation country:
Ardp.202100467
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