Efforts towards a STK10/LOK chemical probe

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 the trisubstituted imidazole compound SB-633825 was identified as a promising hit compound with good potency and selectivity. A three step, divergent and modular synthetic approach was developed to perform SAR studies around the unexplored naphthalene moiety. For this, a small library of 36 new inhibitors has been designed and synthetized based on the SGC crystal structures of STK10 with SB-633825 (PDB ID: 4USE) for testing binding affinity and selectivity evaluation in binding displacement TR-FRET assays. Substituted phenyl analogues were inactive (Ki > 1 uM) and benzo-fused analogues were potent (Ki < 300 nM) but non-selective. The substituted naphthalene analogues were potent (IC50 < 200 nM) while maintaining good selectivity profile against a panel of > 400 kinases