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发现一种用于酪蛋白激酶2的强效且选择性的基于萘啶的化学探针。

Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2.

作者信息

Davis-Gilbert Zachary W, Krämer Andreas, Dunford James E, Howell Stefanie, Senbabaoglu Filiz, Wells Carrow I, Bashore Frances M, Havener Tammy M, Smith Jeffery L, Hossain Mohammad A, Oppermann Udo, Drewry David H, Axtman Alison D

机构信息

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strabe 9, Frankfurt 60438, Germany.

出版信息

ACS Med Chem Lett. 2023 Mar 14;14(4):432-441. doi: 10.1021/acsmedchemlett.2c00530. eCollection 2023 Apr 13.

DOI:10.1021/acsmedchemlett.2c00530
PMID:37077385
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10108397/
Abstract

Naphthyridine-based inhibitors were synthesized to yield a potent and cell-active inhibitor of casein kinase 2 (CK2). Compound selectively inhibits CK2α and CK2α' when profiled broadly, thereby making it an exquisitely selective chemical probe for CK2. A negative control that is structurally related but lacks a key hinge-binding nitrogen () was designed on the basis of structural studies. Compound does not bind CK2α or CK2α' in cells and demonstrates excellent kinome-wide selectivity. Differential anticancer activity was observed when compound was profiled alongside a structurally distinct CK2 chemical probe: SGC-CK2-1. This naphthyridine-based chemical probe () represents one of the best available small molecule tools with which to interrogate biology mediated by CK2.

摘要

合成了基于萘啶的抑制剂，以产生一种有效的、具有细胞活性的酪蛋白激酶2（CK2）抑制剂。该化合物在广泛分析时选择性抑制CK2α和CK2α'，因此使其成为CK2的一种高度选择性的化学探针。基于结构研究设计了一种结构相关但缺少关键铰链结合氮（）的阴性对照。化合物在细胞中不结合CK2α或CK2α'，并表现出优异的全激酶组选择性。当化合物与结构不同的CK2化学探针SGC-CK2-1一起分析时，观察到了不同的抗癌活性。这种基于萘啶的化学探针（）是用于研究由CK2介导的生物学的最佳可用小分子工具之一。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/dca8388a3f88/ml2c00530_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/6d3e2e75311a/ml2c00530_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/cb83b7509af8/ml2c00530_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/9f7d50add46e/ml2c00530_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/e066905b0a14/ml2c00530_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/bccc70ef4903/ml2c00530_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/dca8388a3f88/ml2c00530_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/6d3e2e75311a/ml2c00530_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/cb83b7509af8/ml2c00530_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/9f7d50add46e/ml2c00530_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/e066905b0a14/ml2c00530_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/bccc70ef4903/ml2c00530_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d92b/10108397/dca8388a3f88/ml2c00530_0006.jpg

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