<p>IKK_α, a key component of canonical and non-canonical NFκB signalling, is implicated in prostate cancer and bone metabolism. Here, we validated the anti-proliferative effects of selected molecules from a series of first-in-class IKK_α inhibitors against a panel of human prostate cancer models and then showed that the potent anti-tumour and highly IKK_α-selective SU¹³⁴⁹ reduced the ability of human PC3 cells to migrate and invade in vitro, induce osteolysis ex vivo, and cause trabecular bone loss in mice. Paradoxically, mice treated with SU¹³⁴⁹ exhibited cortical bone loss. Histomorphometrical in vivo and functional in vitro studies confirmed that SU¹³⁴⁹ suppressed osteoclastogenesis, but both enhanced and reduced osteoblast number and activity. Mechanistically, despite SU¹³⁴⁹ being an inhibitor with a significant selectivity for IKK_α over IKK_β, it inhibited both canonical and non-canonical NFκB signalling in PC3 cells, osteoclasts, and osteoblasts, and reduced the levels of several PC3-secreted, NFκB-regulated factors. This study suggests that IKK_α inhibitors could be of therapeutic value in the treatment of prostate cancer-induced osteolysis. However, osteoblast inhibition may limit their usefulness as osteoprotective agents.</p> Graphical Abstract <p></p>