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First-in-Class IKK Alpha Selective Compounds
• First reported potent and selective IKK alpha inhibitors.
• Selective modulation of IKKα PD marker demonstrated in cancer cells.
• Well placed for progression to candidate selection and pre-clinical testing.
We are seeking a co-development or licensing partner to drive candidate selection and entry into formal pre-clinical studies. The programme is led by Professor Simon Mackay at the University of Strathclyde.
The pharmaceutical industry has devoted considerable effort to generating NF-κβ pathway inhibitors and a leading approach has been to target the IκB kinases (IKK). Reported inhibitors have either been pan-IKK inhibitors or IKKβ selective and to date there have been no reports of IKKα selective compounds. Despite being proposed as a target for treating inflammation, inhibition of IKKβ has more recently been associated with a number of side effects including development of inflammatory skin disease and sensitisation of colonic epithelium to a range of insults (Ref 1). In addition IKKβ knockout mice display severe liver toxicity (Ref 2) 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.
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 be of therapeutic benefit. This may enable an informative early stage trial design (further data available under CDA).
The non-canonical (alternative) NF-κβ pathway is controlled by the activity of the I kappa B kinase alpha (IKKα) and is stimulated in response to a range of TNF superfamily cytokines including Lymphotoxin β (LTβ), CD40 ligand (CD40L) and BAFF. There is strong evidence in the literature that in addition to the classical (IKKβ) pathway, in a number of cancers the IKKα driven alternative NF-κB signalling pathway is constitutively active and plays an important role. In a number of leukaemias and lymphomas oncogenic rearrangement of the nfkb2 gene (p100) has been reported and its constitutive activation requires IKKα (Ref 3). Similarly, constitutive activation of the alternative IKKα pathway has been reported in pancreatic cancer (Ref 4) and mutations in the non-canonical pathway are frequent in multiple myloma (Ref 5).
Castrate Resistant Prostate Cancer: Recent data has indicated that Lymphotoxin B, which activates the alternative pathway via IKKα, is an important driver of castrate resistant prostate cancer and may stimulate tumour progression/proliferation following androgen deprivation therapy (Ref 6). Androgen independent prostate cancer lines such as PC3 and DU-145 have also been shown to have constitutive activation of IKKα (Ref 7) and the presence of activated nuclear IKKα has been reported to correlate with more advanced cases of prostate cancer and have a role in driving metastasis (Ref 8). siRNA studies have also confirmed a role for IKK in the
survival and proliferation of androgen independent prostate cancer cell lines further highlighting the attractiveness of this target in prostate cancer.
1. Pubmed ID No: 19855404
2. Pubmed ID No: 10195897
3. Pubmed ID No: 15677466
4. Pubmed ID No: 19646419
5. Pubmed ID No: 17692805
6. Pubmed ID No: 20220849
7. Pubmed ID No: 10602496
8. Pubmed ID No: 17377533