Therapeutic targeting of GSK-3β activation by the tyrosine kinase RYK in pancreatic ductal adenocarcinoma with BJ-2412, a novel sunitinib analogue

Background and purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited treatment options. RYK, an atypical receptor-like tyrosine kinase, has emerged as a potential regulator of tumour signalling, but its role in PDAC remains poorly understood. This study aimed to evaluate the Anticancer potential of BJ-2412, a novel sunitinib analogue with RYK-inhibitory activity, and to elucidate the functional relevance of RYK in PDAC.

Experimental approach: BJ-2412 was synthesized by introducing a 2,4-dimethylpyridin-3-ol moiety into sunitinib. Its Anticancer activity was assessed in PDAC cell lines and mouse tumour models. Mechanistic studies included RTK phosphorylation profiling, RYK knockdown via siRNA, co-immunoprecipitation, immunoblotting of downstream effectors, and analyses of Apoptosis, invasion, and macrophage phenotypes.

Key results: BJ-2412 inhibited RYK phosphorylation by disrupting its interaction with EGFR. While RYK knockdown and BJ-2412 had minimal effects on proliferation, both impaired Cancer cell survival, including that of Cancer Stem Cells. We identified RYK as a GSK-3β Activator that antagonizes canonical Wnt signalling and RTK-mediated GSK-3β inhibition. BJ-2412 inactivated GSK-3β and reduced Sonic Hedgehog (Shh) and GLI1 expression. BJ-2412-induced up-regulation of WNT5A, Cancer cell-selective Apoptosis, M1-macrophage polarization, as well as down-regulation of MMPs and CTSS, were reversed by recombinant Shh. Finally, BJ-2412 suppressed tumour growth, invasion, and metastasis in xenograft and allograft mouse models.

Conclusions and implications: These findings identify RYK as a GSK-3β Activator and a therapeutic vulnerability in PDAC. BJ-2412 demonstrates therapeutic potential by targeting this pathway and remodelling the tumour microenvironment, offering a multifaceted strategy against PDAC progression and resistance.