Synthesis of STK10/LOK inhibitors

The understudied kinase STK10/LOK that is of interest for its role in lymphocyte migration is the target of a chemical probe development effort. In previous work, imidazole compound SB-633825 was identified as lead compound with good potency and selectivity. It was possible to make small improvements in the potency and selectivity however the project hit a roadblock in the chemical synthesis stage. It is mostly desired to modify the naphthalene moiety but it has not been possible to properly explore these possibilities due to restrictions in the original synthetic route which introduced the naphthalene in the first step of a six-step route. A divergent and modular synthetic approach was developed and allows addition of the naphthalene moiety in the final step. A small library of new inhibitors has been designed based on the SGC crystal structures of STK10 with SB-633825 (PDB ID: 4USE) for testing binding affinity and selectivity evaluation.