LAUSR

Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a therapeutic target of interest due to the roles it plays in both neurological diseases and cancer. We present the development of the first macrocyclic inhibitors of DYRK1A. Initial lead inhibitor JH-XIV-68-3 (3) displayed selectivity for DYRK1A and close family member DYRK1B in biochemical and cellular assays, and demonstrated antitumor efficacy in head and neck squamous cell carcinoma (HNSCC) cell lines. However, we noted that it suffered from rapid aldehyde oxidase (AO)-mediated metabolism. To overcome this liability, we generated a derivative (JH-XVII-10 (10)), where fluorine was introduced to block the 2-position of the azaindole and render the molecule resistant to AO activity. We showed that 10 maintains remarkable potency and selectivity in biochemical and cellular assays as well as antitumor efficacy in HNSCC cell lines and improved metabolic stability. Therefore, 10 represents a promising new scaffold for developing DYRK1A-targeting chemical probes and therapeutics.