HTL to candidate

The Target:

The project involved development of an inhibitor of an epigenetic target for treatment of cancer and inflammatory diseases.

Compound Design:

Medicinal chemistry design was driven by the client with input from SYNthesis based on chemical structure where appropriate. Synthetic routes to complex target structures were designed by SYNthesis.

Key Achievements:

• >1200 compounds registered
• 400+ compounds patented from main lead series.
• Lead analogs achieved up to 1000-fold improvement in potency over early hits.
• PK properties successfully optimized to achieve desirable predicted human dose.
• A lead candidate was selected for development along with two backup candidates. Scalable routes to each were developed, to be utilized in process chemistry campaigns.

The Chemistry:

Multiple hit start points with different chemical scaffolds were explored in parallel to identify a lead series, which was achieved in the first six months of the collaboration.  The chemistry largely involved construction of heterocyclic aromatic core templates and preparation/installation of complex heterocycloalkyl functionality, often containing multiple chiral centres. 

Impactful route optimization allowed rapid delivery of samples in 20-50mg quantities with >95% purity for screening and PK studies. This was supported by scale up of key synthetic intermediates to >500g scale. 

In vitro tools compounds such as NanoBRET probes and PROTACs were also prepared, enabling exploration of new technologies within the program.

Scale up of a number of identified lead compounds was successfully conducted to deliver up to 100g of >98% purity material for in-vivo studies whist working to aggressive timelines. This was facilitated by process route development.