2-Aminopyrimidine-5-carboxamides yield a Wee1 inhibitor with strong PLK1 selectivity and oral exposure
- Wee1 supports DNA damage response and cell cycle checkpoints; blocking it removes arrest and promotes mitotic catastrophe.
- A new 2-aminopyrimidine-5-carboxamide series gave lead WC-27, which potently inhibits Wee1 while sparing PLK1, potentially limiting off-target effects and myelosuppression.
- In NCI-H1299 cells it showed adequate antiproliferative activity, S-phase arrest and dose-dependent apoptosis.
- In rats it had favorable pharmacokinetics with good oral bioavailability, low drug-interaction risk and no evident acute toxicity.
💡 Points Based on the abstract
PLK1 selectivity is the right thing to chase here, since Wee1 and PLK1 both land in mitotic control and cell-cycle readouts will blur if an inhibitor hits both. With no binding mode in the abstract, it is unclear whether selectivity comes from the carboxamide or the aminopyrimidine hinge binder. Oral exposure despite only moderate microsomal stability suggests a tractable core; the SAR table will show how far it can be pushed against adavosertib-type chemotypes.