开发用于治疗急性髓系白血病的新型PP2A激活剂。
Development of novel PP2A activators for use in the treatment of acute myeloid leukaemia.
作者信息
Toop Hamish D, Dun Matthew D, Ross Bryony K, Flanagan Hayley M, Verrills Nicole M, Morris Jonathan C
机构信息
School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia and Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
出版信息
Org Biomol Chem. 2016 May 18;14(20):4605-16. doi: 10.1039/c6ob00556j.
AAL(S), the chiral deoxy analog of the FDA approved drug FTY720, has been shown to inhibit proliferation and apoptosis in several cancer cell lines. It has been suggested that it does this by activating protein phosphatase 2A (PP2A). Here we report the synthesis of new cytotoxic analogs of AAL(S) and the evaluation of their cytotoxicity in two myeloid cell lines, one of which is sensitive to PP2A activation. We show that these analogs activate PP2A in these cells supporting the suggested mechanism for their cytotoxic properties. Our findings identify key structural motifs required for anti-cancer effects.
AAL(S)是美国食品药品监督管理局（FDA）批准的药物FTY720的手性脱氧类似物，已被证明可抑制多种癌细胞系的增殖并诱导其凋亡。有人认为它是通过激活蛋白磷酸酶2A（PP2A）来实现这一点的。在此，我们报告了AAL(S)新的细胞毒性类似物的合成及其在两种髓系细胞系中的细胞毒性评估，其中一种对PP2A激活敏感。我们表明，这些类似物在这些细胞中激活了PP2A，支持了其细胞毒性特性的推测机制。我们的研究结果确定了抗癌作用所需的关键结构基序。
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