Differentiated small molecule inhibitor of poly(ADP)ribose glycohydrolase (PARG) which has been developed in collaboration with the Lead Discovery Center (LDC). The target patient populations include indications harbouring homologous recombination deficiencies (HRD), including those resistant to PARP inhibitors as well as an alternative, yet to be disclosed niche patient population. This second clinical development path offers both a differentiation strategy and a target patient population with a significant unmet need. Several small molecules series have been progressed and patents submitted and in vivo POC data exists in models with the HRD phenotype where comparisons with assets in the clinic are favourable.

First-in-class small molecule program modulating GPR68. The target is a proton-sensing GPCR, which plays an integral role in the acidosis process. Strong validation exists demonstrating the central role acidosis plays in disease initiation and progress in areas of inflammation, fibrosis, and tumour growth, particularly colorectal cancer. Previous efforts to develop small molecule modulators lacked structural insights.

This issue was resolved in our program by harnessing the cryo-EM capabilities and proprietary platform of our technology partner, leadXpro in Switzerland. The structure of GPR68 has been elucidated (a world first), which has enabled a structure-based drug design approach, not available to other companies. Three series of small NAMs have been created and moved in to lead optimisation.

This first-in-class small molecule program targets a unique mutant variant, not modulated by other assets in the field. The target represents a precision medicine approach in defined pancreatic and colorectal cancer patient populations. In collaboration with a team of experts from the University of Eastern Finland and harnessing that institution’s proprietary molecular insights and their access to one of Europe’s supercomputers, two hit series of molecules have been identified. Experimental validation against the specific mutational variant of the target has been achieved.

Developed in collaboration with the Lead Discovery Center, this is an early-stage drug discovery program. Inhibition of POLA1 induces chromosomal catastrophe and wide-scale cancer cell death via the induction of replication stress. This novel first-in-class mechanism targets tumours with vulnerabilities that define patient subgroups with high rates of replication stress.