Lee Jeong Tae, Chen David Y, Yang Zhimou, Ramos Alexander D, Hsieh James J-D, Bogyo Matthew
Department of Pathology, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Bioorg Med Chem Lett. 2009 Sep 1;19(17):5086-90. doi: 10.1016/j.bmcl.2009.07.045. Epub 2009 Jul 10.
Taspase1 is a threonine protease responsible for cleaving MLL (Mixed-Lineage Leukemia) to achieve proper HOX gene expression. Subsequent studies identified additional Taspase1 substrates including Transcription Factor IIA (TFIIA) and Drosophila HCF. Taspase1 is essential for cell proliferation and is overexpressed in many cancer cell lines. Currently no small molecule inhibitors of this enzyme have been described. Here, we report the synthesis and evaluation of vinyl sulfone, vinyl ketone, epoxy ketone, and boronic acid inhibitors designed based on the preferred Taspase1 cleavage site (Ac-Ile-Ser-Gln-Leu-Asp). Specifically, we evaluated compounds in which the reactive warhead is positioned in place of the P1 aspartic acid side chain as well as at the C-terminus of the peptide. Interestingly, both classes of inhibitors were effective and vinyl ketones and vinyl sulfones showed the greatest potency for the target protease. These results suggest that Taspase1 has unique substrate recognition properties that could potentially be exploited in the design of potent and selective inhibitors of this enzyme.
Taspase1是一种苏氨酸蛋白酶，负责切割混合谱系白血病蛋白（MLL）以实现适当的HOX基因表达。随后的研究确定了Taspase1的其他底物，包括转录因子IIA（TFIIA）和果蝇HCF。Taspase1对细胞增殖至关重要，并且在许多癌细胞系中过度表达。目前尚未报道该酶的小分子抑制剂。在此，我们报告了基于Taspase1的首选切割位点（Ac-Ile-Ser-Gln-Leu-Asp）设计的乙烯基砜、乙烯基酮、环氧酮和硼酸抑制剂的合成与评估。具体而言，我们评估了其中反应弹头取代P1天冬氨酸侧链以及位于肽C末端的化合物。有趣的是，这两类抑制剂均有效，并且乙烯基酮和乙烯基砜对目标蛋白酶显示出最大的效力。这些结果表明，Taspase1具有独特的底物识别特性，这可能在该酶的强效和选择性抑制剂设计中得到利用。
