Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids
- Author(s)
- Syphers, JL; Wright, JA; Liu, S; Gee, YS; Gao, F; Mudududdla, R; Che, DQ; Chang, A; Sloan, EK; Narasimhan, V; Heriot, A; Ramsay, RG; de Nys, R; Silva, TN; Vrbanac, L; Sammour, T; Lawrence, MJ; Tin, T; Maddern, GJ; Fenix, K; Kaur, H; Barratt, K; Kelter, G; Maier, A; Posch, M; Lu, H; Wang, X; Zhavoronkov, A; Wei, H; Huang, F; Worthley, DL; Priebbenow, DL; Mukherjee, S; Woods, SL; Baell, JB;
- Journal Title
- Journal of Medicinal Chemistry
- Publication Type
- Research article
- Abstract
- 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.
- Publisher
- ACS Publications
- Department(s)
- Laboratory Research; Surgical Oncology
- Publisher's Version
- https://doi.org/10.1021/acs.jmedchem.4c02541
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-05-15 07:59:19
Last Modified: 2025-05-15 07:59:27