Discovery of ZJCK-6-46: A Potent, Selective, and Orally Available Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor for the Treatment of Alzheimer's Disease

  • J Med Chem. 2024 Aug 8;67(15):12571-12600. doi: 10.1021/acs.jmedchem.4c00483.
Huanhua Chen  1 ,  Xudong Gao  2 ,  Xinzhu Li  3 ,  Chong Yu  1 ,  Wenwu Liu  1 ,  Jingsong Qiu  1 ,  Wenjie Liu  1 ,  Hefeng Geng  3 ,  Fangyuan Zheng  3 ,  Hao Gong  1 ,  Zihua Xu  1 ,  Jingming Jia  1 ,  Qingchun Zhao  1  3  2
Affiliations
  • 1. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, Shenyang, Liaoning 110016, P. R. China.
  • 2. Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, China.
  • 3. School of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, Shenyang, Liaoning 110016, P. R. China.
PMID: 39041662 DOI: 10.1021/acs.jmedchem.4c00483
Abstract

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 (ZJCK-6-46) as the most potential DYRK1A inhibitor (IC50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood-brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.

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