Robb Caroline M, Contreras Jacob I, Kour Smit, Taylor Margaret A, Abid Mohammad, Sonawane Yogesh A, Zahid Muhammad, Murry Daryl J, Natarajan Amarnath, Rana Sandeep
Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska 68022, USA.
Chem Commun (Camb). 2017 Jul 4;53(54):7577-7580. doi: 10.1039/c7cc03879h.
Cyclin-dependent kinase 9 (CDK9), a member of the cyclin-dependent protein kinase (CDK) family, is involved in transcriptional elongation of several target genes. CDK9 is ubiquitously expressed and has been shown to contribute to a variety of malignancies such as pancreatic, prostate and breast cancers. Here we report the development of a heterobifunctional small molecule proteolysis targeting chimera (PROTAC) capable of cereblon (CRBN) mediated proteasomal degradation of CDK9. In HCT116 cells, it selectively degrades CDK9 while sparing other CDK family members. This is the first example of a PROTAC that selectively degrades CDK9.
细胞周期蛋白依赖性激酶9（CDK9）是细胞周期蛋白依赖性蛋白激酶（CDK）家族的成员之一，参与多个靶基因的转录延伸。CDK9在全身广泛表达，并且已被证明与多种恶性肿瘤有关，如胰腺癌、前列腺癌和乳腺癌。在此，我们报告了一种异双功能小分子蛋白酶靶向嵌合体（PROTAC）的研发情况，该嵌合体能够通过脑啡肽（CRBN）介导蛋白酶体降解CDK9。在HCT116细胞中，它能选择性地降解CDK9，而不影响其他CDK家族成员。这是选择性降解CDK9的PROTAC的首个实例。
