Every year, 1.5 million people are diagnosed with colorectal cancer, and 44% die within five years. A team at the Institute of Cancer Research, working with Domainex, has developed a new class of drug-like compounds that block tankyrase 1 and 2, enzymes that drive the Wnt signalling pathway—a key growth signal active in 90% of colorectal tumours. These small molecules inhibit tumour cell growth in the low nanomolar range and have already shown effectiveness in animal models. The problem is that no drug currently targets this pathway effectively. This project will select the best compound from a novel chemistry series, run a full preclinical testing programme, and take it into a Phase 1 clinical trial. If successful, these tankyrase inhibitors could become the first oral treatment for Wnt-driven colorectal cancers. The compounds may also work against tumours with BRCA1 or BRCA2 mutations, and early evidence suggests broader applications in cardiac repair, pulmonary fibrosis, and neurodegenerative diseases—though those remain distant possibilities.
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1.5 million new cases of colorectal cancer (CRC) are diagnosed annually. 44% of these patients die within five years of their diagnosis, despite the identification of mutations that drive CRC. For example, 90% of colorectal tumours carry mutations that drive constitutive Wnt signalling, yet efforts to pharmacologically target this pathway have, until recently, proven difficult. To address this area of unmet need, we have identified drug like, small molecule inhibitors of tankyrase 1 and 2 (TNKS1/2) that restrict Wnt signalling and inhibit colorectal tumour cell growth. Tankyrase inhibition also has the potential to target tumour cells carrying BRCA1 or BRCA2 gene mutations. Finally, tankyrase inhibitors also modulate cellular phenotypes associated with cardiac repair, pulmonary fibrosis and neurodegenerative diseases, suggesting a much wider application for drug like tankyrase inhibitors outside the oncology setting. Already the ICR, in collaboration with Domainex (Perrior, Jarvis), has developed drug-like preclinical compounds that inhibit tankyrase in the low nanomolar range and suppress in vivo tumour cell growth in a xenograft model system. Wellcome Trust funding for this first stage of work will cease on 28th Feb 2013. During this phase the team has also identified novel compounds that have enhanced cellular efficacy in terms of effects on Wnt-dependent transcription. This enhanced effect on Wnt-dependent transcription also translates into an enhanced effect on the level of Wnt-dependent tumour cell inhibition (sub-500 nM SF50 in HT55 cells). For these latter compounds, combining this cellular efficacy profile with optimal pharmacokinetics has the potential to demonstrate increased in vivo therapeutic efficacy and generate a superior follow-on clinical candidate. Given the nature of these newer compounds, the Trust has invited the applicants to outline a plan that is aimed at selecting the best candidate from this novel chemistry and to take this through a full pre-clinical testing programme as well as an initial (Phase 1) stage of clinical assessment. This application describes the strategy.
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