Inhibition of Her2 Transcription by Small Organic Molecules

摘要

Overexpression of the Her2 protein has been found in 30% of breast tumors, and the inhibition of Her2 expression may be an effective way to treat Her2-positive patients. Recently, the P.1. and co-workers reported identification of chemical inhibitors of Her2 transcription. The compounds that we named adamanolol and wrenchnolol inhibited Her2 transcription by disrupting the interaction of two cancer-linked nuclear proteins, ESX and Sur-2. Affinity purification revealed that wrenchnolol binds to the Sur-2 subunit of the human mediator complex by mimicking the potent activation domain of transcription factor ESX. In the third year of finding, we designed a STF1 (synthetic transcription factor), taking advantage of the ability of wrenchnolol to bind to the Sur-2 subunit and the specific DNA-binding affinity of a hairpin polyamide molecule. The hybrid compound of these two molecules activated transcription of a reporter gene in vitro in a promoter-dependent manner through simultaneous contacts with DNA and Sur-2. Our results indicate that wrenchnolol serves as an activation domain mimic, and that it is possible to generate a transcription factor out of completely organic components.