Benzamide derivatives of thioacridine as DYRK2 and DYRK3 dual inhibitors

TY - JOUR

T1 - Benzamide derivatives of thioacridine as DYRK2 and DYRK3 dual inhibitors

AU - Roussel, Jean

AU - Kashyap, Shreya

AU - Banerjee, Sourav

AU - Lomberget, Thierry

AU - Hallé, François

N1 - © 2025 Wiley‐VCH GmbH.

PY - 2025/6/17

Y1 - 2025/6/17

N2 - DYRK2 has become a promising therapeutic target due to its involvement in various processes, including regulation of protein stability and phosphorylation events related to neurodegenerative diseases and cancers. The thioacridine derivative LDN-192960 has been widely recognized as a potent inhibitor of DYRK2. However, it also inhibits other kinases, such as DYRK3, Haspin, DYRK1A, and CLK1, making it challenging to delineate the biological roles of DYRK2. Herein, a series of benzamide derivatives of the thioacridine LDN-192960 are designed and synthesized to improve selectivity and potency toward DYRK2. Several compounds demonstrate potent inhibition of DYRK2 and DYRK3, with IC 50 values in the nanomolar range. Notably, the para-substituted aldehyde derivative 10f exhibits significant selectivity for DYRK2/DYRK3 against its main off-targets DYRK1A, CLK1, and Haspin, thus surpassing the selectivity profile of LDN-192960. Docking studies reveal new interactions between 10f and DYRK2, compared to LDN-192960/DYRK2 cocrystallized structure, and 10f is shown to impair proteasome activity in HEK293 cells. These findings highlight the pharmacophore study of DYRK2/DYRK3 dual inhibitors and present compound 10f as a selective chemical probe for DYRK2 and DYRK3, which might be an essential tool for elucidating the specific biological roles of these kinases and advancing targeted therapeutic applications.

AB - DYRK2 has become a promising therapeutic target due to its involvement in various processes, including regulation of protein stability and phosphorylation events related to neurodegenerative diseases and cancers. The thioacridine derivative LDN-192960 has been widely recognized as a potent inhibitor of DYRK2. However, it also inhibits other kinases, such as DYRK3, Haspin, DYRK1A, and CLK1, making it challenging to delineate the biological roles of DYRK2. Herein, a series of benzamide derivatives of the thioacridine LDN-192960 are designed and synthesized to improve selectivity and potency toward DYRK2. Several compounds demonstrate potent inhibition of DYRK2 and DYRK3, with IC 50 values in the nanomolar range. Notably, the para-substituted aldehyde derivative 10f exhibits significant selectivity for DYRK2/DYRK3 against its main off-targets DYRK1A, CLK1, and Haspin, thus surpassing the selectivity profile of LDN-192960. Docking studies reveal new interactions between 10f and DYRK2, compared to LDN-192960/DYRK2 cocrystallized structure, and 10f is shown to impair proteasome activity in HEK293 cells. These findings highlight the pharmacophore study of DYRK2/DYRK3 dual inhibitors and present compound 10f as a selective chemical probe for DYRK2 and DYRK3, which might be an essential tool for elucidating the specific biological roles of these kinases and advancing targeted therapeutic applications.

KW - Acridine Kinase DYRK Selectivity Inhibitors

KW - selectivity

KW - inhibitors

KW - kinase

KW - DYRK

KW - acridine

UR - https://www.scopus.com/pages/publications/105004357743

U2 - 10.1002/cmdc.202500122

DO - 10.1002/cmdc.202500122

M3 - Article

C2 - 40145237

SN - 1860-7179

VL - 20

JO - ChemMedChem

JF - ChemMedChem

IS - 12

M1 - e202500122

ER -