Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling.
Cell Chem Biol
; 31(7): 1247-1263.e16, 2024 Jul 18.
Article
in En
| MEDLINE
| ID: mdl-38537632
ABSTRACT
This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription Factors
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Signal Transduction
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Adaptor Proteins, Signal Transducing
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Cell Proliferation
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High-Throughput Screening Assays
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YAP-Signaling Proteins
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Antineoplastic Agents
Limits:
Animals
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Humans
Language:
En
Journal:
Cell Chem Biol
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: