Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction |
| |
Authors: | Jihye Lee Yijiang Shi Mario Vega Yonghui Yang Joseph Gera Michael E Jung Alan Lichtenstein |
| |
Institution: | 1. Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA;2. Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA;3. Jonnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA;4. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA;5. Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA 91343, USA |
| |
Abstract: | DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein–protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast. This therapeutic (compound B) also prevented DEPTOR/mTOR binding in MM cells and was selectively cytotoxic to MM cells. We now present a structure–activity relationship (SAR) study around this compound as a follow-up report of this previous work. This study has led to the discovery of five new leads – namely compounds 3g, 3k, 4d, 4e and 4g – all of which have anti-myeloma cytotoxic properties superior to compound B. Due to their targeting of DEPTOR, these compounds activate mTORC1 and selectively induce MM cell apoptosis and cell cycle arrest. |
| |
Keywords: | mTOR DEPTOR Multiple myeloma Cytotoxicity SAR study |
本文献已被 ScienceDirect 等数据库收录! |
|