DEPTOR与mTOR相互作用的小分子抑制剂的构效关系研究
Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction.
作者信息
Lee Jihye, Shi Yijiang, Vega Mario, Yang Yonghui, Gera Joseph, Jung Michael E, Lichtenstein Alan
机构信息
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.
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.
出版信息
Bioorg Med Chem Lett. 2017 Oct 15;27(20):4714-4724. doi: 10.1016/j.bmcl.2017.09.002. Epub 2017 Sep 6.
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.
DEPTOR是一种48kDa的蛋白质，它与mTOR结合并在mTORC1和mTORC2复合物中抑制这种激酶。DEPTOR的过表达特别发生在多发性骨髓瘤（MM）肿瘤模型中，并且敲低DEPTOR对MM细胞具有细胞毒性，这表明它是一个潜在的治疗靶点。由于mTORC1失活可保护MM细胞免受DEPTOR敲低的影响，这表明DEPTOR与mTOR之间的蛋白质-蛋白质相互作用是MM细胞存活与死亡的关键。在先前的一项研究中，我们使用酵母双杂交筛选一个小型抑制剂文库，以鉴定一种能在酵母中抑制DEPTOR/mTOR结合的化合物。这种治疗性化合物（化合物B）也能阻止MM细胞中的DEPTOR/mTOR结合，并且对MM细胞具有选择性细胞毒性。我们现在围绕该化合物进行结构-活性关系（SAR）研究，作为这项先前工作的后续报告。这项研究发现了五个新的先导化合物——即化合物3g、3k、4d、4e和4g——所有这些化合物都具有优于化合物B的抗骨髓瘤细胞毒性特性。由于它们靶向DEPTOR，这些化合物激活mTORC1并选择性诱导MM细胞凋亡和细胞周期停滞。
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