Discovery of the First Potent DYRK2 Proteolysis Targeting Chimera Degraders

Jian Chen; Wentao Zhu; Wenqian Zhang; Yichen Tong; Fang Xu; Jiyan Pang

doi:10.1021/acsmedchemlett.4c00065

Discovery of the First Potent DYRK2 Proteolysis Targeting Chimera Degraders

ACS Med Chem Lett. 2024 Apr 30;15(5):659-666. doi: 10.1021/acsmedchemlett.4c00065. eCollection 2024 May 9.

Authors

Jian Chen¹, Wentao Zhu¹, Wenqian Zhang¹, Yichen Tong¹, Fang Xu², Jiyan Pang¹

Affiliations

¹ School of Chemistry, Sun Yat-sen University, Guangzhou 510275, China.
² International Cooperative Laboratory of Traditional Chinese Medicine Modernization & Innovative Drug Development of Chinese Ministry of Education (MOE) and Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.

PMID: 38746900
PMCID: PMC11089551 (available on 2025-05-09)
DOI: 10.1021/acsmedchemlett.4c00065

Abstract

Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been identified as a promising oncogenic driver of several types of cancer and is considered to be a critical cancer therapeutic target. Several inhibitors of DYRK2 have been reported, but no degraders have been found yet. In this work, we designed and synthesized the first series of proteolysis-targeting chimeras (PROTACs) using curcumin and its analogs as warheads to target and degrade DYRK2. The results of degradation assays showed that the compound CP134 could effectively downregulate the intracellular DYRK2 level (DC₅₀ = 1.607 μM). Further mechanism of action experiments revealed that CP134 induced DYRK2 degradation through the ubiquitin-proteasome system. Altogether, CP134 disclosed in this study is the first potent DYRK2 degrader, which could serve as a valuable chemical tool for further evaluation of its therapeutic potential, and our results broaden the substrate spectrum of PROTAC-based degraders for further therapeutic applications.