Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells,Journal of Medicinal Chemistry

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Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-04-28 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01613
Matthias Bach ₁ , Anna Lehmann ₂ , Daniela Brünnert ₃ , Jens T. Vanselow ₁ , Andreas Hartung ₂ , Ralf C. Bargou ₄ , Ulrike Holzgrabe ₂ , Andreas Schlosser ₁ , Manik Chatterjee ₃

Affiliation

Heat shock transcription factor 1 (HSF1) has been identified as a therapeutic target for pharmacological treatment of multiple myeloma (MM). However, direct therapeutic targeting of HSF1 function seems to be difficult due to the shortage of clinically suitable pharmacological inhibitors. We utilized the Ugi multicomponent reaction to create a small but smart library of α-acyl aminocarboxamides and evaluated their ability to suppress heat shock response (HSR) in MM cells. Using the INA-6 cell line as the MM model and the strictly HSF1-dependent HSP72 induction as a HSR model, we identified potential HSF1 inhibitors. Mass spectrometry-based affinity capture experiments with biotin-linked derivatives revealed a number of target proteins and complexes, which exhibit an armadillo domain. Also, four members of the tumor-promoting and HSF1-associated phosphatidylinositol 3-kinase-related kinase (PIKK) family were identified. The antitumor activity was evaluated, showing that treatment with the anti-HSF1 compounds strongly induced apoptotic cell death in MM cells.

中文翻译：

Ugi反应衍生的α-酰基氨基羧酰胺与磷脂酰肌醇3-激酶相关的激酶结合，抑制HSF1依赖性热休克反应，并诱导多发性骨髓瘤细胞凋亡。

热休克转录因子1（HSF1）已被确定为多发性骨髓瘤（MM）药理治疗的治疗靶标。但是，由于缺乏临床上合适的药理学抑制剂，直接治疗靶向HSF1功能似乎很困难。我们利用Ugi多组分反应创建了一个小型但灵巧的α-酰基氨基羧酰胺文库，并评估了其抑制MM细胞中热休克反应（HSR）的能力。使用INA-6细胞系作为MM模型，并严格依赖HSF1的HSP72诱导作为HSR模型，我们确定了潜在的HSF1抑制剂。使用生物素连接的衍生物进行的基于质谱的亲和力捕获实验揭示了许多靶蛋白和复合物，它们均表现出犰狳结构域。还，确定了促进肿瘤和与HSF1相关的磷脂酰肌醇3-激酶相关激酶（PIKK）家族的四个成员。评价抗肿瘤活性，表明用抗HSF1化合物治疗强烈诱导MM细胞中凋亡细胞死亡。

更新日期：2017-05-09

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