Article
作者: Ramsay, Robert G. ; Maddern, Guy J. ; Sammour, Tarik ; Sloan, Erica K. ; Mudududdla, Ramesh ; Fenix, Kevin ; Wright, Josephine A. ; Mukherjee, Siddhartha ; Syphers, Joel L. ; Liu, Shen ; Heriot, Alexander ; Gao, Fan ; Wang, Xiaomin ; Wei, Heping ; Kelter, Gerhard ; Lawrence, Matthew J. ; Kaur, Harleen ; Huang, Fei ; Posch, Markus ; Narasimhan, Vignesh ; Priebbenow, Daniel L. ; Silva, Tharindie N. ; Woods, Susan L. ; de Nys, Rebekah ; Worthley, Daniel L. ; Maier, Armin ; Baell, Jonathan B. ; Chang, Aeson ; Tin, Teresa ; Zhavoronkov, Alex ; Lu, Hongfu ; Barratt, Kate ; Gee, Yi Sing ; Che, Da Qing ; Vrbanac, Laura
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.