Targeting DEPTOR in myeloma

DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Over-expression of DEPTOR specifically occurs in a model of multiple myeloma (MM). Its silencing in MM cells is sufficient to induce cytotoxicity, suggesting DEPTOR is a potential therapeutic target. mTORC1 paralysis protects MM cells against DEPTOR silencing, implicating mTORC1 in DEPTOR's critical role in MM cell viability. Building on this foundation, we interrogated a small molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay. One compound was identified that also prevented DEPTOR-mTOR binding in human myeloma cells with subsequent activation of mTORC1 and mTORC2. In a surface plasmon resonance (SPR) assay, the compound bound to recombinant DEPTOR but not to mTOR. The drug also prevented binding of recombinant DEPTOR to mTOR in the SPR assay. Remarkably, although activating TORC1 and TORC2, the compound induced apoptosis and cell cycle arrest in MM cell lines and prevented outgrowth of human MM cells in immunodeficient mice. In vitro cytotoxicity against MM cell lines was directly correlated with DEPTOR protein expression and was mediated, in part, by the activation of TORC1 and induction of p21 expression. Additional cytotoxicity was seen against primary MM cells while normal hematopoietic colony formation was unaffected. These results further support DEPTOR as a viable therapeutic target in MM and suggest an effective strategy of preventing binding of DEPTOR to mTOR.

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