Background: Metastatic castrate-resistant prostate cancer (mCRPC), defined by the failure of androgen signaling inhibitor therapy to maintain the control of disease, is incurable. The extensive heterogeneity of mCRPC underlies the difficulty in identifying effective therapeutics that target the ‘intrinsic’ genetic drivers of disease. Inflammation is a key biological feature of mCRPC, promoting cell survival, therapeutic resistance and establishment of an immunosuppressive landscape that impedes the effectiveness of immunotherapy. We hypothesise that disrupting the complex inflammatory signalling networks driving mCRPC progression provides a disease-relevant therapeutic intervention. IKKα is an intracellular kinase that critically regulates both inflammatory cytokine production and coupling cytokine signalling to activation of the non-canonical NF-kB pathway. Moreover, IKKα is highly activated in mCRPC patients with high expression correlating with shorter time-to-death-from-relapse (p=0.047). This correlation is more pronounced in androgen receptor (AR)-amplified and high-proliferating tumours, suggesting it may be a potential therapeutic target.
Results: Through an extensive medicinal chemistry programme, we have developed a first-in-class small-molecule inhibitor, SU1644, which exhibits high potency and selectivity for IKKα without perturbing the IKKβ-driven canonical NF-κB pathway. This was validated by SU1644-mediated attenuation of the NFκB2 p100 processing to p52 across a panel of prostate cancer (PCa) cells. In vitro assays confirm SU1644 reduces cell proliferation in all examined PCa cell lines (IC50=0.23-0.37 μM) and monocyte-derived immune cell lineages. Functionally, SU1644 induces cell cycle arrest at G2/M phase and promotes apoptosis in PCa cells. Notably, SU1644 reduces AR expression at both transcriptional and translational levels (including the AR-V7 variant), attenuates nuclear AR distribution, and decreases AR-mediated gene transcription in PCa cells. Compared to the standard-of-care anti-androgen agent, Enzalutamide, SU1644 exhibits greater potency and significantly enhances its efficacy. Finally, SU1644 induces a robust, dose-dependent anti-tumour response in ex vivo patient-derived explants (n=9; p<0.01).
Conclusions: SU1644 demonstrates effective suppression of the non-canonical NF-kB pathway and AR expression/signalling in multiple PCa cell lines, and has potent anti-cancer activity in PCa cells, monocytic immune cells and ex vivo patient derived explants. Our results indicate this proprietary IKKα-selective inhibitor offers a new avenue for advancing mCRPC treatment strategies by overcoming both intrinsic and extrinsic inflammation-associated resistance mechanisms.