Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2024

Discovery of DYRK1A Inhibitors as Potential Treatment of Pancreatic Ductal Adenocarcinoma (PDAC) (#205)

Hsing-Pang Hsieh 1 , Yu-Xiang Zhang-Jian 1 , Kai-Cheng Hsu 2 , Shiow-Lin Pan 2 , Wen-Shan Li 3 4 , Han-Chung Wu 4 5
  1. Institute of Biotech and Pharma Research, National Health Research Institutes, Miaoli County, Taiwan
  2. GraduaInstitute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
  3. Institute of Chemistry, Academia Sinica, Taipei, Taiwan
  4. Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei, Taiwan
  5. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) belongs to the CMGC family of eukaryotic protein kinases and is an attractive therapeutic target due to its roles in both neurodegenerative diseases and cancers. Based on the activity of DYRK1A interactors and substrates, it is assumed that DYRK1A is a pleiotropic protein with widespread cellular functions, including the regulation of cell proliferation, survival, and differentiation.

In a recent study, DYRK1A was shown to be upregulated in pancreatic ductal adenocarcinoma (PDAC), providing evidence that DYRK1A favors tumor progression. In a PANC-1-shDYRK1A xenograft animal model, reduced levels of DYRK1A impaired proliferation, leading to slower tumor progression. These results prompted the discovery of DYRK1A inhibitors for the treatment of PDAC.

In this study, we designed and synthesized a series of DYRK1A inhibitors. The structure-activity relationship (SAR) study results showed that PANDK103 exhibited excellent DYRK1A inhibitory ability with an IC50 value of 7.8 nM, 40-fold greater than INDY, the known reference compound. Currently, we have achieved acceptable pharmacokinetic data. Further hit-to-lead optimization and pharmacokinetics studies are in progress and will be reported in due course.

  1. Jarhad, D. B.; Mashelkar, K. K.; Kim, H.-R.; Noh, M.; Jeong, L. S. Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics. J. MED. Chem, 2018, 61, 9791–9810.