Are you developing or thinking of developing small molecule therapeutics against a really challenging target? If so, does one of these scenarios describe your situation?

• You are trying to determine which small molecule approach is best for your target (orthosteric/allosteric inhibitor, degrader, inhibitory complex formation).
• You are wondering whether a molecular glue (MG) approach would work for your target.
• You tried a molecular glue screen but it did not work.

We think what you need is a fast, painless way to determine if fragments can be effective MGs for your target plus a desired partner. We have developed an extremely sensitive, biophysics based approach to screen a fragment library for compounds that can synergistically stabilize binding between arbitrary pairs of proteins. The entire process, from assay development to delivery of confirmed hits only requires 2 months.

Our biophysical assay for MG screening uses SPR to detect fragments that selectively act as MGs. The assay is designed such that binding signal is entirely dependent on a compound exhibiting synergistic binding (quantified as the alpha factor) to the PAIR of proteins, a hallmark of a molecular glue. ZoBio has embarked on a program of screening its highly validated fragment library for de novo MG discovery using this selective assay. To date we have performed 12 screens on different protein pairs with our roughly 1,800 compound fragment library. Of these, 10 have generated validated MG hits exhibiting alpha factors between 5 (cutoff) and 40. We have seen that when the two proteins have an intrinsic affinity for each other better than 1 mM, there is a 100% correlation with finding validated MG hits.

We would like to use our hard-earned expertise to help enable your Molecular Glue programs. To do so we have put together a fast, low hurdle trajectory to a clear Go/No Go decision. The workflow consists of producing the proteins or using your preparations, setting up an SPR assay and determining if there is intrinsic affinity between the proteins better than 1 mM. If so, we screen our fragment library and titrate selected hits to confirm alpha factors >5. The entire process can be completed in 2 months, once the proteins are available.