| Autor: |
Angelica V. Carmona, Shirisha Jonnalagadda, Alfie M. Case, Krishnaiah Maddeboina, Sravan K. Jonnalagadda, Louise F. Dow, Ling Duan, Trevor M. Penning, Paul C. Trippier |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Communications Chemistry, Vol 7, Iss 1, Pp 1-10 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2399-3669 |
| DOI: |
10.1038/s42004-024-01177-4 |
| Popis: |
Abstract Aldo-keto reductase 1C3 (AKR1C3) is a protein upregulated in prostate cancer, hematological malignancies, and other cancers where it contributes to proliferation and chemotherapeutic resistance. Androgen receptor splice variant 7 (ARv7) is the most common mutation of the AR receptor that confers resistance to clinical androgen receptor signalling inhibitors in castration-resistant prostate cancer. AKR1C3 interacts with ARv7 promoting stabilization. Herein we report the discovery of the first-in-class AKR1C3 Proteolysis-Targeting Chimera (PROTAC) degrader. This first-generation degrader potently reduced AKR1C3 expression in 22Rv1 prostate cancer cells with a half-maximal degradation concentration (DC50) of 52 nM. Gratifyingly, concomitant degradation of ARv7 was observed with a DC50 = 70 nM, along with degradation of the AKR1C3 isoforms AKR1C1 and AKR1C2 to a lesser extent. This compound represents a highly useful chemical tool and a promising strategy for prostate cancer intervention. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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