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开发一种针对多效性激酶 CK2 的有效且选择性的化学探针。

Development of a potent and selective chemical probe for the pleiotropic kinase CK2.

机构信息

Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill (UNC-CH), Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, UNC-CH, Chapel Hill, NC 27599, USA.

Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany; Structural Genomics Consortium, Buchman Institute for Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.

出版信息

Cell Chem Biol. 2021 Apr 15;28(4):546-558.e10. doi: 10.1016/j.chembiol.2020.12.013. Epub 2021 Jan 22.

DOI:10.1016/j.chembiol.2020.12.013
PMID:33484635
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8864761/
Abstract

Building on the pyrazolopyrimidine CK2 (casein kinase 2) inhibitor scaffold, we designed a small targeted library. Through comprehensive evaluation of inhibitor selectivity, we identified inhibitor 24 (SGC-CK2-1) as a highly potent and cell-active CK2 chemical probe with exclusive selectivity for both human CK2 isoforms. Remarkably, despite years of research pointing to CK2 as a key driver in cancer, our chemical probe did not elicit a broad antiproliferative phenotype in >90% of >140 cell lines when tested in dose-response. While many publications have reported CK2 functions, CK2 biology is complex and an available high-quality chemical tool such as SGC-CK2-1 will be indispensable in deciphering the relationships between CK2 function and phenotypes.

摘要

基于吡唑并嘧啶 CK2（酪蛋白激酶 2）抑制剂骨架，我们设计了一个小型靶向文库。通过对抑制剂选择性的全面评估，我们鉴定出抑制剂 24（SGC-CK2-1）是一种高效且具有细胞活性的 CK2 化学探针，对两种人源 CK2 同工酶均具有独特的选择性。值得注意的是，尽管多年的研究表明 CK2 是癌症的关键驱动因素，但当我们以剂量反应方式在 >140 种细胞系中进行测试时，我们的化学探针并未引发 >90%的细胞系表现出广泛的抗增殖表型。虽然许多出版物都报道了 CK2 的功能，但 CK2 生物学非常复杂，因此像 SGC-CK2-1 这样的高质量化学工具将是解析 CK2 功能与表型之间关系不可或缺的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6c/8864761/475c11b74e82/nihms-1660533-f0005.jpg
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