Malignant mesothelioma cell lines frequently have mutations of the NF2 genes associated with Hippo signaling pathway; consequently, YAP (Yes-associated protein) is constantly activated. In order to develop an antimesothelioma drug, we attempted protein knockdown strategy using SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser) molecules, which consist of ligands for IAP and target protein, and linker moiety binding the two ligands. The SNIPER molecule is able to induce IAP's ubiquitin ligase ubiquitinating for the target protein, leading to subsequent degradation by the proteasome.<br/> In this study, we designed and synthesized the new SNIPER molecules for degradation of YAP and investigated degradation activities of these compounds. To explore optimal distance between IAP binding site and YAP ligand, we synthesized some SNIPER molecules with linkers in several lengths. From a result of growth inhibition of NCl-H290 cells, it was suggested that the synthesized SNIPER molecule with a certain linker length have degradation activity for YAP.

Design and synthesis of SNIPER intended for degradation of YAP

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.