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

Area of Science:

• Biochemistry
• Oncology
• Pharmacology

Background:

• DEPTOR (DEP domain-containing mTOR-interacting protein) is a 48kDa protein that inhibits mTOR kinase activity in both mTORC1 and mTORC2 complexes.
• DEPTOR overexpression is specific to multiple myeloma (MM) and its knockdown is cytotoxic to MM cells, identifying it as a potential therapeutic target.
• The interaction between DEPTOR and mTOR is critical for MM cell viability, as mTORC1 inhibition protects MM cells from DEPTOR knockdown-induced death.

Purpose of the Study:

• To conduct a structure-activity relationship (SAR) study on a previously identified DEPTOR/mTOR inhibitor (compound B).
• To discover novel compounds with enhanced anti-myeloma cytotoxic properties.
• To investigate the mechanism of action of newly identified lead compounds.

Main Methods:

• Yeast two-hybrid screening of a small inhibitor library to identify DEPTOR/mTOR binding inhibitors.
• Structure-activity relationship (SAR) analysis of lead compounds.
• Assessment of anti-myeloma cytotoxic properties and mechanism of action in MM cells.

Main Results:

• A novel compound (compound B) was identified that inhibits DEPTOR/mTOR binding in yeast and MM cells, exhibiting selective cytotoxicity.
• The SAR study identified five new lead compounds (3g, 3k, 4d, 4e, 4g) with superior anti-myeloma activity compared to compound B.
• These new compounds target DEPTOR, activate mTORC1, and selectively induce MM cell apoptosis and cell cycle arrest.

Conclusions:

• Targeting the DEPTOR-mTOR interaction is a promising therapeutic strategy for multiple myeloma.
• The newly discovered lead compounds demonstrate significant potential for further development as anti-myeloma agents.
• These compounds offer a novel approach to induce MM cell death through selective apoptosis and cell cycle arrest.