| abstract |
The present invention relates to the ability to regulate any protein of interest in living systems with small molecules. In particular, the present invention relates to the discovery that appending a hydrophobic moiety to the surface of a protein can mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. An aspect of the present invention relates to bifunctional small molecules that bind a number of proteins, including, for example, a self-labeling tag such as bacterial dehalogenase (HaloTag protein) and present a hydrophobic group on its surface. Hydrophobic tagging of the HaloTag protein with a hydrophobic moiety (e.g. an adamantyl moiety) was effected and the tagging induced the degradation of cytosolic, isoprenylated, and transmembrane fusion proteins in cell culture. The present invention also demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting RasG12V-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models. |