Identification of a peptoid inhibitor of the proteasome that targets Sug2/Rpt4 Sub-unit

MEDI 303

Hyun-Suk Lim, hyun-suk.lim@utsouthwestern.edu1, Chase T. Archer1, Di Cai1, Deirdre Brekken1, and Thomas Kodadek2. (1) Division of Translational Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, (2) Department of Internal Medicine and Division of Translational Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390
The 26S proteasome is a large, multi-protein complex comprised of a 20S catalytic complex capped on each end with a 19S regulatory particle (RP) that is responsible for most non-lysosomal proteolysis in mammalian cells. The 19S RP, which have protein unfolding activity, play non-proteolytic roles independent of the 20S core particle (CP) in transcription and DNA repair. The active site in the 20S CP is the target of recently developed drugs for the treatment of cancer. However, there have been no reports of pharmacological mediators of the 19S RP, which might also be interesting as research tools or perhaps even drug leads. Here we describe the isolation of such a molecule, called RIP-1, from a combinatorial library. RIP-1 is shown to inhibit the activity of the 19S RP in vitro as well as the proteolytic activity of the proteasome in living cells. Chemical cross-linking experiments identified the molecular target of RIP-1 as Sug2/Rpt4, one of the six ATPases.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007