Cancer Selective Target Degradation by Folate-Caged PROTACs.
J Am Chem Soc
; 143(19): 7380-7387, 2021 05 19.
Article
em En
| MEDLINE
| ID: mdl-33970635
ABSTRACT
PROTACs (proteolysis targeting chimeras) are an emerging class of promising therapeutic modalities that degrade intracellular protein targets by hijacking the cellular ubiquitin-proteasome system. However, potential toxicity of PROTACs in normal cells due to the off-tissue on-target degradation effect limits their clinical applications. Precise control of a PROTAC's on-target degradation activity in a tissue-selective manner could minimize potential toxicity/side-effects. To this end, we developed a cancer cell selective delivery strategy for PROTACs by conjugating a folate group to a ligand of the VHL E3 ubiquitin ligase, to achieve targeted degradation of proteins of interest (POIs) in cancer cells versus noncancerous normal cells. We show that our folate-PROTACs, including BRD PROTAC (folate-ARV-771), MEK PROTAC (folate-MS432), and ALK PROTAC (folate-MS99), are capable of degrading BRDs, MEKs, and ALK, respectively, in a folate receptor-dependent manner in cancer cells. This design provides a generalizable platform for PROTACs to achieve selective degradation of POIs in cancer cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirrolidinas
/
Tiazóis
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Ubiquitina-Proteína Ligases
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Inibidores Enzimáticos
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Ácido Fólico
/
Neoplasias
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos