Distinct binding modes of a benzothiazole derivative confer structural bases for increasing ERK2 or p38α MAPK selectivity.

Autor: Hasegawa S; Graduate School of Science, Osaka Metropolitan University, Osaka, 599-8570, Japan., Yoshida M; Graduate School of Science, Osaka Metropolitan University, Osaka, 599-8570, Japan., Nagao H; Carna Biosciences, Inc., Kobe, 650-0047, Japan., Sugiyama H; Mitsubishi Chemical Corporation, Yokohama, 227-8502, Japan., Sawa M; Carna Biosciences, Inc., Kobe, 650-0047, Japan., Kinoshita T; Graduate School of Science, Osaka Metropolitan University, Osaka, 599-8570, Japan. Electronic address: kinotk@omu.ac.jp.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Apr 16; Vol. 704, pp. 149707. Date of Electronic Publication: 2024 Feb 22.
DOI: 10.1016/j.bbrc.2024.149707
Abstrakt: Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2) and p38α MAP kinase (p38α MAPK), regulate various cellular responses. ERK2 is a drug target for treating many diseases, such as cancer, whereas p38α has attracted much attention as a promising drug target for treating inflammatory disorders. ERK2 is a critical off-target for p38α MAPK and vice versa. In this study, an allosteric ERK2 inhibitor with a benzothiazole moiety (compound 1) displayed comparable inhibitory activity against p38α MAPK. Crystal structures of these MAPKs showed that compound 1 bound to the allosteric site of ERK2 and p38α MAPK in distinct manners. Compound 1 formed a covalent bond with Cys162 of p38α MAPK, whereas this covalent bond was absent in the ERK2 complex even though the corresponding cysteine is conserved in ERK2. Structural dissection combined with computational simulations indicated that an amino acid difference in the allosteric site is responsible for the distinct binding modes of compound 1 with ERK2 and p38α MAPK. These structural insights underline the feasibility of developing highly selective and potent ERK2 and p38α MAPK inhibitors.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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