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.

DEPTOR是一种48 kDa蛋白，与mTOR结合并抑制mTORC1和mTORC2复合物中的该激酶。DEPTOR的过度表达特别发生在多发性骨髓瘤（MM）肿瘤模型中，而DEPTOR敲低对MM细胞具有细胞毒性，表明它是潜在的治疗靶标。由于mTORC1麻痹可保护MM细胞免受DEPTOR的敲低，这表明DEPTOR和mTOR之间的蛋白质相互作用是MM生存力与死亡的关键。在先前的研究中，我们使用了一个小型抑制剂库的酵母双杂交筛选来鉴定抑制酵母中DEPTOR / mTOR结合的化合物。这种治疗剂（化合物B）还阻止了MM细胞中DEPTOR / mTOR的结合，并对MM细胞具有选择性的细胞毒性。现在，我们围绕该化合物提出结构-活性关系（SAR）研究，作为该先前工作的后续报告。这项研究导致发现了五种新的前导物，即化合物3g，3k，4d，4e和4g，它们均具有优于化合物B的抗骨髓瘤细胞毒性特性。由于它们以DEPTOR为靶标，因此可以激活mTORC1和选择性诱导MM细胞凋亡和细胞周期停滞。