Objective

Constant improvement of systems is essential in drug development, requiring the feedback of past successes and failures. However, when an acquired screening hit compound is modified, the resultant lead compound is not always annotated with the original structure. As a result, when a compound is declared as a lead, its original acquisition source might be unknown, thus preventing acquisition strategies from being revised accordingly. We aim to develop a reliable system using Chemical Space Networks (CSN's), to annotate declared leads with most likely hits by creating a pathway that allows us to work backwards using a number of known examples. Once confident of the progression pathway, identification of confirmed leads will enable us to work backwards to identify the screening hits. Acquisition sources of hit compounds can then be found using internal applications to create acquisition metrics as well as to advise on future acquisition strategies.

Methods

Aim: To develop a reliable system to annotate declared leads with likely hits by creating a pathway that allows us to work backwards from the Lead Compounds to the Screening Hits using a number of known examples. Once confident of the progression pathway, obtaining lists of confirmed leads will enable us to work backwards. By using these lists of leads to identify the hits, we can track back to see whether these hits were CCE samples and in turn create metrics displaying the number of CCE samples that have progressed as hits & leads, per year for the last 5/10 years. Find hit and analogue compounds: Optimization assays are known from lead. Collection of potential compounds can be returned. Those with high throughput screening records are potential hits. Chemical space networks (CSN): CSNs visually represent compounds with connections for defined properties. SmallWorld by NextMove Software connects compounds based on structural refinements. Filters set to connect compounds 2 or less refinements apart. Connections represent reasonable structure change in a step of a progression pathway. All pathways from potential hits to lead can be identified. Compounds along these progressions can be inspected using properties such as Date, pIC50/potency, Property forecast index (PFI). Progressions are then assigned a value to quantify their validity Comparison reveals the most likely hit compound. Acquisition source of Hit Compound can be identified using internal applications.

Results

Identify trends and collate CCE metrics for last 5-10 years.

Conclusion

Successful progression pathways give us the ability to advise on future acquisition strategies.