Dual-specificity tyrosine phosphorylation-regulated kinase 1A(DYRK1A) belongs to the CMGC family of eukaryotic protein kinases and is an attractive therpaeutic 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 favours tumour progression. in a PANC-1-shDYRK1A xenograft animal model, reduced levels of DYRK1A impaired proliferation, leading to slower tumour 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 eshibited excellent DYRK1A inhibitory ability with an IC50 value of 7.8nM, 40-fold greater than INDY, the known reference compound. Currently, we have achieved acceptable pharmacokinetic data. Further hit-to-ead optimization and pharmacokinetics studies are in progress and will be reported in due course.
Date:
2024-11-07
Relation:
Asia-Pacific Journal of Clinical Oncology. 2024 Nov 07;20:116.
