Case Study 1: CCK2

novel chemotypes from known actives

Cresset's field technology can generate new leads when other approaches fail. It is ideal for GPCRs and ion channels which lack x-ray data of the target. One example comes from our collaboration with the James Black Foundation.

Search molecules for CCK2

The James Black Foundation required new leads for CCK2, a peptide-ligand GPCR target, for which no protein structural information was available. Cresset determined the likely binding conformation for three known actives at the target using FieldTemplater™. The actives used in the FieldTemplater™ study were both in-house compounds and competitor compounds gleaned from patents. Two of the three molecules were then selected for use as search molecules for screening using FieldScreen ™.

Hits for CCK2

The FieldScreen™ search took field patterns from these two molecules and searched through a library of >600,000 commercially-available compounds. A list of the best scoring 1,000 compounds was provided to the client, who screened just 88 compounds which were selected from the result set on the basis that they has no structural similarity to any known CCK2 actives. Of these 88, 27 (30%) were hits, with pK_b >5 (better than 10uM). Most of the hits had no structural similarity to any known CCK2 active compounds: these were totally new scaffolds which could be developed clear of competitors patents. Three of the compounds which were not chosen for further development are shown to demonstrate the structural diversity of the hits.

These results demonstrate how Cresset's technology can kick-start in a drug discovery program for minimal investment in compound acquisition and screening.