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Horizon Discovery and C4X to harness CRISPR for new cancer drugs

UK companies combine computational and genomic platforms


Gene-editing specialists Horizon Discovery is to work with C4X Discovery to exploit CRISPR-Cas9 and other novel technologies to develop new oncology candidates.

The two UK-based companies are among a new generation of firms looking to use new drug discovery capabilities based on computer modelling and genomic tools to accelerate drug discovery and early development timelines,

C4X Discovery (C4XD), a spin-out from the University of Manchester, has developed its drug discovery software platform Taxonomy3, which uses human genetic datasets to identify novel patient-specific targets while Cambridge-based Horizon has its own proprietary gene editing and gene modulation technologies.

Horizon has used its target discovery platform to conduct CRISPR gene knock-out studies across multiple cancer cell lines, screening around ~3000 genes suitable as the basis for small molecule drug targets. This cutting-edge approach has identified a shortlist of around 20 novel, high value synthetic lethal genes following a secondary screen to further validate them as targets.

The partners aims to validate novel targets identified by Horizon against ‘synthetic lethality’ – a mechanism proven to be clinically and commercially successful by the poly(ADP-ribose) polymerase (PARP) inhibitors, led by AstraZeneca’s Lynparza.

These work by targeting a specific DNA repair pathway that cancer cells, with mutations such as BRCA, become over-reliant on. Inhibiting this critical DNA repair pathway causes the tumour cells to self-destruct, hence the term 'synthetic lethality'.

Horizon and C4X say pharma companies are now using traditional empirical research to identify other compounds which can produce this effect – but claim their techniques can make this process much faster.

The partners will work on oncology targets that Horizon has identified using its CRISPR-Cas9 technology, with C4XD then using its proprietary 4D shape-based chemistry technology (Conformetrix) to discover pre-clinical drug candidates.

The companies say they will be focused on discovering new compounds in therapy areas with treatments of limited effectiveness, such as colorectal and lung cancer.

Recent advancements in the gene-editing tool, CRISPR-Cas9, has enabled systematic 'functional genomic' screening to identify novel synthetic lethal genes in cancer cells with specific mutations.

Dr Craig Fox, Chief Scientific Officer of C4XD, said: "PARP inhibitors are transforming the treatment of ovarian cancer, particularly in patients with BRCA mutations and so identifying the next generation of synthetic lethality drug targets is a key priority to develop new therapies for cancer patients who are not responsive to current treatments.”

The partnership has been established to complete the target validation package for these novel targets, leading to the start of drug discovery programmes by C4XD should it exercise its options on a target-by-target basis.

C4XD will fund the work plan and if it discovers pre-clinical drug candidates for these novel, synthetic lethality targets, it will out-license them to clinical development partners, with Horizon receiving an undisclosed share of revenue received by C4XD.

C4XD has already had success in this strategy, having signed an outlicensing agreement with Indivior for a pre-clinical addiction programme worth up to $294m.

Jon Moore

Jon Moore

“Drugging the cancer genome now requires new synthetic lethal therapies that can exploit the vulnerabilities in patient's tumours that are created by mutations in undruggable cancer driver gene,” said Dr Jon Moore, Horizon's Chief Scientific Officer.

The partnership gives C4XD access to Horizon’s proprietary CRISPR screening dataset that has selected the most promising novel drug targets in colon and lung cancer.

Article by
Andrew McConaghie

18th December 2018

From: Research



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