基于氨基吡唑的 CDK9 PROTAC 使胰腺癌细胞对 venetoclax 敏感。
Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax.
机构信息
Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA.
Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE 68022, USA.
出版信息
Bioorg Med Chem Lett. 2021 Jul 1;43:128061. doi: 10.1016/j.bmcl.2021.128061. Epub 2021 Apr 23.
Abstract
Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition.
摘要
周期蛋白依赖性激酶 9（CDK9）是周期蛋白依赖性激酶（CDK）家族的一员，参与多个基因的转录调控，包括癌基因 Myc，是胰腺癌的一个已验证的靶点。在这里，我们报告了一种基于氨基吡唑的蛋白水解靶向嵌合体（PROTAC 2）的开发，该嵌合体选择性降解 CDK9（DC=158±6 nM）。基于质谱的激酶组谱分析显示，PROTAC 2 选择性地在 MiaPaCa2 细胞中降解 CDK9，并使它们对 Venetoclax 介导的生长抑制敏感。
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