2. Academic Validation
  3. Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction

Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction

  • Bioorg Med Chem Lett. 2017 Oct 15;27(20):4714-4724. doi: 10.1016/j.bmcl.2017.09.002.
Jihye Lee 1,  Yijiang Shi 2,  Mario Vega 3,  Yonghui Yang 3,  Joseph Gera 4,  Michael E Jung 5,  Alan Lichtenstein 6
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, 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; Jonnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 3 Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 4 Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA 91343, USA.
  • 5 Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: jung@chem.ucla.edu.
  • 6 Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA 91343, USA. Electronic address: alan.lichtenstein@med.va.gov.
PMID: 28916338 DOI: 10.1016/j.bmcl.2017.09.002
Abstract

DEPTOR is a 48kDa 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

Cytotoxicity; DEPTOR; Multiple myeloma; SAR study; mTOR.

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