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 (1), many of which were more selective for WEE1 over an undesirable
off-target of 1, the kinase PLK1. When tested against
patient-derived organoids (PDOs) grown from TP53-mutated
colorectal cancer (CRC) peritoneal metastases, 34 (IC50 value of 62 nM) exhibited stronger efficacy than 1 (IC50 value of 120 nM) and the best-in-class clinical
candidate ZN-c3 (IC50 value of 127 nM). Against primary
CRC PDOs with TP53-WT, 34 significantly
enhanced DNA damage, replication stress and apoptosis compared to 1, 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.