Structural insights for producing CK2α1-specific inhibitors

Masato Tsuyuguchi; Tetsuko Nakaniwa; Akira Hirasawa; Isao Nakanishi; Takayoshi Kinoshita

doi:10.1016/j.bmcl.2019.126837

Structural insights for producing CK2α1-specific inhibitors

Bioorg Med Chem Lett. 2020 Jan 15;30(2):126837. doi: 10.1016/j.bmcl.2019.126837. Epub 2019 Dec 3.

Authors

Masato Tsuyuguchi¹, Tetsuko Nakaniwa², Akira Hirasawa³, Isao Nakanishi⁴, Takayoshi Kinoshita⁵

Affiliations

¹ Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan. Electronic address: tsuyuguchi13@b.s.osakafu-u.ac.jp.
² Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
³ Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
⁴ Faculty of Pharmacy, Department of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
⁵ Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

PMID: 31859160
DOI: 10.1016/j.bmcl.2019.126837

Abstract

Casein kinase 2 catalytic subunit (CK2α) is classified into two subtypes CK2α1 and CK2α2. CK2α1 is a drug discovery target, whereas CK2α2 is an off-target of CK2α1 inhibitors. High amino acid sequence homology between these subtypes hampers efforts to produce ATP competitive inhibitors that are highly selective to CK2α1. Hematein was identified previously as a non-ATP-competitive inhibitor for CK2α1, whereas this compound acts as an ATP competitive CK2α2 inhibitor. Crystal structures of CK2α1 and CK2α2 in complex with hematein revealed distinct binding features that provide structural insights for producing CK2α1-selective inhibitors.

Keywords: Binding mode; CK2α1; Conformational change; Crystal structure; Selectivity.

MeSH terms

Amino Acid Sequence
Casein Kinase II / antagonists & inhibitors
Humans
Models, Molecular

Substances

CSNK2A1 protein, human
Casein Kinase II