C4XD aims to apply its proprietary 4D shape-based chemistry technology (Conformetrix) to discover drug candidates directed against these high value, novel, synthetic lethality targets and out-license them to clinical development partners. This discovery partnership bolsters C4XD’s oncology pipeline, a high priority therapeutic area for the company.
The therapeutic concept of harnessing synthetic lethality in cancer with tumour-specific mutations has been demonstrated with the recent approval of the poly(ADP-ribose) polymerase (PARP) inhibitors Lynparza® Zejula® and Rubraca®. These drugs are effective in indications that are poorly served by immunotherapy drugs, such as checkpoint inhibitors, and have become an established treatment in ovarian cancer. They 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, resulting in the terminology ‘synthetic lethality’. The pharmaceutical industry is now rushing to fill its clinical pipelines with investigational drugs, identified by empirical research, that might produce similar efficacy in cancers where PARP inhibitors are not effective.
However, 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. Horizon has utilised its target discovery platform to conduct high quality 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 ~20 novel, high value synthetic lethal genes following a secondary screen to further validate them as targets. The partnership has been established to complete the target validation package for these novel targets, leading to the initiation of drug discovery programmes by C4XD should it exercise its options on a target-by-target basis. C4XD will provide the funding for the work plan and Horizon will receive a share of all future revenues C4XD receives should any drug discovery programmes emerging from the partnership be out-licensed for clinical development.
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 cancers patients who are not responsive to current treatments. This partnership with Horizon gives C4XD access to a comprehensive proprietary CRISPR screening dataset that has selected the most promising novel drug targets in colon and lung cancer. We look forward to working with the highly experienced team at Horizon to complete the target validation package for these novel genes and initiate drug discovery programmes to generate high value pre-clinical licensable assets for partnering.”
Dr Jon Moore, Horizon’s Chief Scientific Officer added: “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 genes. Horizon’s internal research program has used powerful CRISPR technology to open a new window into how cancer cells are wired and has identified a cohort of novel targets. We are delighted to have secured this collaboration with C4X Discovery, which applies a powerful drug discovery engine to the first-in-class opportunities for transformational medicines represented by the targets Horizon has found and allows Horizon to share in the upside.”