Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids
Joel L. Syphers, Josephine A. Wright, Shen Liu, Yi Sing Gee, Fan Gao, Ramesh Mudududdla, Da Qing Che, Aeson Chang, Erica K. Sloan, Vignesh Narasimhan, Alexander Graham Heriot, Robert George Ramsay, Rebekah de Nys, Tharindie N. Silva, Laura Vrbanac, Tarik Sammour, Matthew James Lawrence, Teresa Tin, Guy John Maddern, Kevin Aaron Fenix · Journal of Medicinal Chemistry · 2025
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 (IC 50 value of 62 nM) exhibited stronger efficacy than 1 (IC 50 value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC 50 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.