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First-in-Class IKK Alpha Selective Compounds
We have developed first-in-class IKKα selective compounds with in vivo data showing strong inhibition of tumour growth. We are seeking a licensing/co-development partner to support key biological data and drive candidate selection for clinical and regulatory development.
The pharmaceutical industry has devoted considerable effort toward generating NF-κβ pathway inhibitors, and a leading approach has been to target the IκB kinases (IKK), focused on either pan-IKK or IKKβ-selective inhibitors. However, inhibition of IKKβ has been associated with a number of side effects, including development of inflammatory skin disease and sensitisation of colonic epithelium to a range of insults. In addition, IKKβ knockout mice display severe liver toxicity, and reports suggest intestinal and liver toxicity has been an issue in clinical trials of IKKβ inhibitors. 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, and selectivity over IKKβ may help facilitate 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.