Pustelny, K. | bioRxiv Science

bioRxiv2024

Curcumin Inhibition of DYRK Kinases

Curcumin is known as a dietary supplement with several health benefits, including antioxidant, blood sugar-lowering, anti-inflammatory, and anti-cancer properties. These benefits make it useful in the treatment of diabetes, neurodegenerative diseases, and cancer. This research focuses on how curcumin interacts with dual-specificity tyrosine-regulated kinases (DYRKs), particularly DYRK1A and DYRK2, which control important cellular processes such as protein breakdown, gene activity and DNA packaging. DYRK1A is crucial for the growth and survival of pancreatic {beta}-cells, which are key in the treatment of diabetes. Curcumin helps increase insulin release and sensitivity by affecting these cells. DYRK2, on the other hand, is involved in cancer, where curcumins ability to block its activity helps to reduce tumour growth and spread. These interactions demonstrate curcumins potential as a versatile treatment option. By affecting DYRK1A and DYRK2, curcumin promotes {beta}-cell health in diabetes and fights cancer by inhibiting cell growth and promoting cell death. This study underscores the promise of curcumin as a natural compound for treating complex diseases associated with oxidative stress and inflammation, highlighting the need for a better understanding of DYRK kinases to effectively exploit their role in disease processes and cell signalling.

molecular biology↗

bioRxiv2022

Structural perspective on the design of selective DYRK1B inhibitors.

DYRK1B has been recently recognized as a critical therapeutic target in oncology and non-alcoholic fatty liver disease. However, the lack of structural information has constrained the development of selective inhibitors for DYRK1B. Here, we employed recombinant protein production, activity assays, and crystallization to elucidate the structure of DYRK1B. We present a crystal structure of DYRK1B in complex with a known inhibitor, AZ191. For comparative analysis, we provide the crystal structure of the closely related DYRK1A kinase in complex with AZ191. Our analysis identifies the exclusiveness of the binding site in the hinge region of DYRK1B, which is pivotal for selective inhibitor design. Quantum mechanical calculations reveal a notable difference in the accessibility of the catalytic lysine between DYRK1B and DYRK1A, offering avenues for distinguishing binders to these kinases. Our findings mark a significant advancement in the quest for specific DYRK1B inhibitors, potentially offering focused efficacy compared to the current dual-specificity inhibitors targeting both DYRK1B and DYRK1A.

biochemistry↗