Rational Design and Synthesis of Selective Macrocyclic WEE1 Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids

WEE1 kinase is an enticing target for cancer therapy due to its critical role in regulating the cell cycle. However, the previous frontrunner clinical candidate AZD1775, a potent WEE1 inhibitor, failed in Phase 2 trials owing to patient tolerability issues, purportedly resulting from off-target inhibition of the structurally related kinase PLK1. To address this limitation, a computer-guided design strategy was employed to help develop macrocyclic derivatives of AZD1775, aiming to enhance target selectivity. These novel macrocycles exhibited markedly improved selectivity for WEE1 over PLK1 and demonstrated potent anticancer activity against patient-derived organoids grown from colorectal cancer peritoneal and liver metastases.