Bispecific Small Molecules

APPLICATION TO METABOLIC DISEASE

Evolution of a bispecific molecule. The height of each bar indicates model scores for a panel of targets from two distinct enzyme families (cyan and teal colours). Potency requirements for both primary targets are indicated by grey lines.

Evolution of a bispecific molecule. The height of each bar indicates model scores for a panel of targets from two distinct enzyme families (cyan and teal colours). Potency requirements for both primary targets are indicated by grey lines.

Our dual target approach is exemplified by the design of a bispecific small molecule that inhibits a novel combination of two metabolic disease enzymes from distinct gene families.

There was no precedence for a single molecule with integrated pharmacophore being able to bind to these targets.

The design process for a bispecific molecule is similar to our approach for single targets. The key difference is that potency must simultaneously satisfy two different targets. 

The graph above depicts the evolution of a compound series to achieve the required potency whilst simultaneously maintaining selectivity, ADME, Ligand Efficiency and associated properties.

An early design exhibited nanomolar inhibition at both targets (Enzyme A: IC50= 347nM and Enzyme B: IC50= 11nM)  and came from a series with opportunity for further refinement.

To understand how the same compound is able to bind two unrelated proteins both protein-ligand complexes were solved by x-ray crystallography (see below).

A <400 Molecular Weight compound with nanomolar potency for both primary targets. Binding was confirmed by X-ray crystallography. 

A <400 Molecular Weight compound with nanomolar potency for both primary targets. Binding was confirmed by X-ray crystallography.