임현석 교수

The first chemical inhibitor of the 19S regulatory particle (RP) of the proteasome is described. The molecule was identified by screening a library of nucleoside-capped peptoids for binding to the yeast 26S proteasome in a crude extract. The hit was resynthesized and shown to block 19S RP-mediated protein unfolding in vitro and proteasome-mediated turnover of p27 in HeLa cells.

Here we describe a simple method that allows for rapid and easy sequence determination of cyclic peptoids. The key idea in this strategy is a post-screening "ring-opening" reaction to convert cyclic peptoids selected from a high-throughput screen into linear peptoids, which can be sequenced by tandem mass spectrometry. Thus, there is no need for encoding.

Skp2 is thought to have two critical roles in tumorigenesis. As part of the SCF(Skp2) ubiquitin ligase, Skp2 drives the cell cycle by mediating the degradation of cell cycle proteins. Besides the proteolytic activity, Skp2 also blocks p53-mediated apoptosis by outcompeting p53 for binding p300. Herein, we exploit the Skp2/p300 interaction as a new target for Skp2 inhibition. An affinity-based high-throughput screen of a combinatorial cyclic peptoid library identified an inhibitor that binds to S

Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through

This study describes the identification of the protein target of the first chemical inhibitor (RIP-1) of the 19S regulatory particle (RP) of the 26S proteasome. Periodate-triggered chemical cross-linking of DOPA-conjugated RIP-1 and the 26S proteasome identified Sug2/Rpt4, one of the six ATPases in the 19S RP as the molecular target of RIP-1. The specificity of RIP-1 for Sug2/Rpt4 was demonstrated by examining cross-linking reactions with each ATPase of the 19S RP. RIP-1 should provide a useful

A facile solid phase synthesis of 2,4,6,7-tetrasubstituted pyrrolo[2,3-d]pyrimidines is described. The synthesis involves a highly efficient five-step route starting from resin-bound dimeric peptoids. To demonstrate the versatility of our method, a representative library of 108 tetrasubstituted pyrrolo[2,3-d]pyrimidines of high quality was synthesized.

Here we report a simple and effective method to identify the minimal pharmacophore in the first peptoid inhibitor of the 19S proteasome regulatory particle, which has led to the development of a derivative that exhibits improved cellular activity, presumably due to a reduction in mass of about two-fold and the elimination of positively charged lysine-like residues.

A novel submonomer solid-phase synthetic method for α-ABpeptoid oligomers is reported. Iterative submonomer coupling and Fukuyama-Mitsunobu alkylation enable facile, divergent synthesis of α-ABpeptoid oligomers substituted with chemically diverse side chains in excellent yields.

Herein, we report a strategy for generating conformationally restricted α-helix mimetic small molecules by introducing covalent bridges that limit rotation about the central axis of α-helix mimetics. We demonstrate that the bridged α-helix mimetics have enhanced binding affinity and specificity to the target protein due to the restricted conformation as well as extra interaction of the bridge with the protein surface.