You have just completed a fragment screen and titrated your hits for confirmation. You have 15 chemotypes you want to follow up on, so you set out to find 10 close analogs for each one. Since this is early days, you don’t want to commit to chemistry, so you search for available compounds. After a week you manage to find an average of 7 for each chemotype by loosening your definition of close and you click the “confirm order” button. Now you wait 6-7 weeks, or in biotech years, an eternity.

This is a standard scenario in nearly any screening modality, but particularly so in fragments where initial confirmed hits are typically very weak binders (>500 mM). In this case, it is essentiall to validate a chemotype through analoging before committing to a full campaign. But waiting 6-7 weeks for analogs to arrive can be a showstopper in some situations. At ZoBio, we have set out to eliminate this problem by building a library of about 10 close analogs for each of the 900 chemotypes in our fragment screening deck. For us, close is defined as a maximum of 3 heavy atoms different from the deck compound.

To date we have assembled a little more than 11% of the analog library, which will eventually number some 9,000 compounds. However, even at this level of coverage we already have cases where a significant number of desired analogs are off the shelf available (Figure 1.) In this case, 119 of the roughly 330 desired analogs (10 per scaffold in the 33 compound hit list) were present at ZoBio and were titrated within days of receiving a “Go” decision from the client.

In another case, we had 2 interesting scaffolds in the hit list from the screen each with K_D >1 mM. We had 6 analogs of 1 scaffold and 7 of the other scaffold in our collection. Each of these series yielded 2 compounds with K_Ds < 1 mM (0.9 and 0.5 mM) and we were able to obtain the crystal structures of all 4 of these analogs, all within 3 weeks of completing the initial screen of the fragment library.

At ZoBio we pride ourselves in recognizing our client’s pain points and deriving unique, effective solutions to them. The FAST library (Fragment Analogs for Scaffold Triaging) is a great example of how we can reduce your timelines while increasing confidence in a fragment campaign.

Interested? Let’s get in touch.