Preprint: Nitrile Analogues of Avapritinib Engage the Catalytic Lysine of KIT
- In this unreviewed preprint, avapritinib's pyrimidine core was swapped for a nitrile-bearing aromatic scaffold so KIT's catalytic lysine could act as an anchor that resistance mutations may spare.
- Crystal structures showed the nitrile pointing at that lysine and reorienting the ligand in the ATP site, with kinase inhibition preserved, including against some mutants.
- Squaric ester analogues labeled KIT covalently in a time-, concentration- and pH-dependent way, and ATP-site occupancy reduced the earliest labeling event.
💡 Points
A nitrile reaching the catalytic lysine is a smart way around gatekeeper and activation-loop mutations, yet the new ATP-site pose probably costs avapritinib's selectivity, so a kinome panel comes first. Squaric esters are the weak link: hydrolytically fragile and prone to hitting surface lysines. Does ATP-competitive labeling hold in cells, not just buffer?
Structural Basis for Nitrile-Directed Recognition of the Catalytic Lysine in KIT ↗