基于肽的 MALT1 连接酶半胱天冬酶共价抑制剂。
Peptide-based covalent inhibitors of MALT1 paracaspase.
机构信息
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Boston, MA 02115, USA.
Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
出版信息
Bioorg Med Chem Lett. 2019 Jun 1;29(11):1336-1339. doi: 10.1016/j.bmcl.2019.03.046. Epub 2019 Mar 29.
Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPR-fmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Example compounds showed good overall selectivity towards cysteine proteases, and one compound was selected for further profiling in ABL-DLBCL cells and xenograft efficacy models.
我们从四肽工具化合物 Z-VRPR-fmk 开发出了强效且选择性基于底物的 MALTI 蛋白酶共价抑制剂。为了提高细胞通透性，我们替换了一个精氨酸残基。我们进一步优化了一系列三肽，并鉴定出了在 GloSensor 报告基因测定法（用于测量细胞 MALTI 蛋白酶活性）和 OCI-Ly3 细胞增殖测定法中均具有强效的化合物。代表性化合物对半胱氨酸蛋白酶表现出了良好的整体选择性，并且选择了一种化合物在 ABL-DLBCL 细胞和异种移植功效模型中进行进一步分析。
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