First-in-Class IKK alpha selective compounds
We are seeking a licensing/co-development partner to support key biological data and drive candidate selection for clinical and regulatory development.
Highlights
- Primary clinical hypothesis: use of IKKα inhibitors for the treatment of castrate resistant prostate cancer (CRPC) and resistance to androgen ablation therapies (e.g. abiraterone, enzalutamide etc)
- Additional targeted indications: pancreatic cancer, multiple myeloma, CLL, colorectal cancer, triple negative breast cancer
- Compounds demonstrate in-vivo efficacy in a prostate cancer model
- Scaffold/series in clear chemical space and discussions with patent agents underway re filing on series
The opportunity
IKKα is a key kinase in the non-canonical NF-κB signalling pathway which drives signalling from TNF family receptors such as CD40, lymphotoxin Beta, RANK and BAFFR. Given the growing evidence that IKKα has an important role in a number of cancers, the development of selective IKKα inhibitors is an attractive approach, with selectivity over IKKβ potentially key in facilitating use of such compounds clinically.
We have now developed the first reported potent and selective IKK alpha inhibitors, and our lead compound has been shown to achieve 60% tumour growth inhibition in the metastatic PC3m xenograph prostate cancer model, despite its current sub-optimal PK (optimisation is ongoing). Consistent with this, in vitro studies have demonstrated a reduction in androgen receptor levels. Intriguingly, our scientists have identified a major cohort of prostate cancer patients with a specific molecular marker who have a significantly worse prognosis and in which an IKKα inhibitor could therefore potentially be of therapeutic benefit. This may enable an informative early stage trial design (further data available under CDA).
In vitro data, including inhibition of colony formation and the induction of apoptosis, have implicated IKK alpha in a variety of other cancers, including pancreatic and colorectal cancers and leukaemia. Preliminary data in a primary tumour ex vivo study has shown induction of apoptosis in range of pancreatic cancer cell lines.
The programme is led by Professor Simon Mackay at the University of Strathclyde.