Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids.

A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (), many of which were more selective for WEE1 over an undesirable off-target of , the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from -mutated colorectal cancer (CRC) peritoneal metastases, (IC value of 62 nM) exhibited stronger efficacy than (IC value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC value of 127 nM). Against primary CRC PDOs with -WT, significantly enhanced DNA damage, replication stress and apoptosis compared to , as well as demonstrated high selectivity over patient-matched normal healthy colon PDOs, highlighting a potential therapeutic window for cancer treatment. Overall, this investigation provides critical insight into several potent WEE1 inhibitors that exhibited exceptional efficacy against CRC PDOs and is the first to utilize a PDO platform to assess their effect on healthy and malignant cell viability.