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

Jihye Lee; Yijiang Shi; Mario Vega; Yonghui Yang; Joseph Gera; Michael E Jung; Alan Lichtenstein

doi:10.1016/j.bmcl.2017.09.002

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. Epub 2017 Sep 6.

Authors

Jihye Lee¹, Yijiang Shi², Mario Vega³, Yonghui Yang³, Joseph Gera⁴, Michael E Jung⁵, Alan Lichtenstein⁶

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.

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Apoptosis / drug effects
Cell Line, Tumor
Humans
Inhibitory Concentration 50
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins / metabolism*
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Multiprotein Complexes / antagonists & inhibitors
Multiprotein Complexes / metabolism
Phosphorylation / drug effects
Protein Binding
Protein Tyrosine Phosphatases / metabolism
RNA Interference
RNA, Small Interfering / metabolism
Regulatory-Associated Protein of mTOR
Small Molecule Libraries / chemistry
Small Molecule Libraries / metabolism*
Small Molecule Libraries / pharmacology
Structure-Activity Relationship
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / metabolism*

Substances

Adaptor Proteins, Signal Transducing
Intracellular Signaling Peptides and Proteins
Multiprotein Complexes
RNA, Small Interfering
RPTOR protein, human
Regulatory-Associated Protein of mTOR
Small Molecule Libraries
DEPTOR protein, human
MTOR protein, human
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
TOR Serine-Threonine Kinases
Protein Tyrosine Phosphatases
UBASH3B protein, human

Abstract

MeSH terms

Substances

Grants and funding