A formidable toolkit exists for manipulating protein expression at the transcriptional level, but the methods for the post-translational modulation of proteins are few and of limited utility. A small molecule that induces degradation of endogenous proteins would clearly be a tremendously useful tool for probing protein function and an exciting approach for chemotherapy. The challenge is to develop technology that is biocompatible and widely applicable. We have serendipitously discovered a moiety that when combined with a recognition element, induces degradation of the target protein. We propose to characterize this phenomenon and develop these novel tools for protein knockdown that will be invaluable in a broad array of biological and pharmaceutical applications.
The ability to manipulate protein levels is invaluable in investigations of biological function, so if successful, this proposal will have an enormous impact in the basic science arena. The potential impact in drug discovery is also substantial: the ability to induce the degradation of pathogenic proteins is expected to be much more effective treatment than current inhibition strategies. The promise of such an approach is readily apparent in the treatment of cancer and hereditary diseases.
|Coffey, Rory T; Shi, Yuntao; Long, Marcus J C et al. (2016) Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling. J Biol Chem 291:5221-33|
|Lawson, Ann P; Long, Marcus J C; Coffey, Rory T et al. (2015) Naturally Occurring Isothiocyanates Exert Anticancer Effects by Inhibiting Deubiquitinating Enzymes. Cancer Res 75:5130-42|
|Long, Marcus J C; Gollapalli, Deviprasad R; Hedstrom, Lizbeth (2012) Inhibitor mediated protein degradation. Chem Biol 19:629-37|