Within the drug discovery process, typically, an active core structure is established and alterations around the core are performed to improve properties of interest. Scaffold hopping is an approach used to explore new chemistry around the core (/scaffold) of interest in the hope of retaining similar properties with slight structural changes. Scaffolds are typically a ring system or systems that can sometimes be connected by linkers. There have been several studies examining the potential ring chemical space and replacements.

MedChemica is a pioneer and advocate of using Matched Molecular Pairs (MMPs) within the drug discovery process. By exploiting MMPs, MedChemica have developed software called RuleDesign® that performs small chemical transformations to improve the properties of an input molecule. Within RuleDesign®, transformations are only applied if there is a high certainty of improvement in the property of interest. This is determined using statistical analysis on the MMPs and measurement data. Core changes, however, are relatively rare events in the life of any project, as they usually require a completely different synthetic start point, therefore, the number of matched pairs for any core change is inevitably low. To address this, CoreDesign® extends RuleDesign® by relaxing the probability of a successful core or linker change transformation improving the property of interest by including all possible transformations but requiring an associated literature reference. Therefore, CoreDesign® prioritises core exchanges with good synthetic tractability alongside a bibliography of other instances where this transformation occurred so users can understand whether this transformation is applicable.

This talk will explain how we have used CoreDesign® to design new cores for the two new PROTACs that have gone into clinical trials, ARV-110 and ARV-471. The PROTAC linker was selected as the core to design new potential scaffolds on, as in this instance, the other two key features, E3 ligase ligand and a ligand for target protein are essential for binding.

An example of a CoreDesign® transformation, where the core is highlighted in yellow

Jessica Stacey

PhD Student, University of Sheffield

Appearances