A novel aurora kinase molecular glue-based degrader sp-2-067 inhibits prostate cancer cell growth and alters immune...

Aurora Kinase A (AKA) is overexpressed in prostate cancer and promotes disease progression through oncogenic pathways and immune modulation. AKA inhibition faces challenges in clinical trials, and alternate methods, such as degradation, may overcome some of these barriers. We evaluated SP-2-067, a novel selective AKA degrader, in C4-2 prostate cancer cells using viability assays, Western blot analysis, and siRNA knockdown. SP-2-067's dose- and time-dependent effects on AKA, related proteins (AUNIP and NINEIN) and immune checkpoint (IC) proteins (PD-L1 and LAG3) were quantified. In silico analysis of TCGA datasets examined the clinical link of the AKA axis and its correlation with immune cell infiltration in prostate cancer. SP-2-067 demonstrated potent dose-dependent anti-proliferative effects. The compound selectively degraded AKA over Aurora Kinase B (AKB) with sustained effects at 72 h. Treatment induced marked PD-L1 upregulation (~ 20-fold at 3 h) and concurrent LAG3 downregulation. siRNA experiments confirmed these effects were AKA-dependent. TCGA analysis revealed AKA, AUNIP, and NINEIN overexpression in prostate cancer correlates with distinct immune-cell infiltration. SP-2-067 is a novel, selective AKA degrader that modulates IC expression by upregulating PD-L1 and downregulating LAG3, indicating its potential for immunomodulation through AUNIP- and NINEIN-mediated mechanisms. Additionally, AKA, AUNIP, and NINEIN are linked to a distinct immune cell profile, presenting an opportunity to reshape the tumor immune microenvironment and support combinatorial strategies with IC inhibitors in prostate cancer.