Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids
Date
2025
Authors
Syphers, J.L.
Wright, J.A.
Liu, S.
Gee, Y.S.
Gao, F.
Mudududdla, R.
Che, D.Q.
Chang, A.
Sloan, E.K.
Narasimhan, V.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Medicinal Chemistry, 2025; 68(8):8065-8090
Statement of Responsibility
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 Heriot, Robert G. Ramsay, Rebekah de Nys, Tharindie N. Silva, Laura Vrbanac, Tarik Sammour, Matthew J. Lawrence, Teresa Tin, Guy J. Maddern, Kevin Fenix, Harleen Kaur, Kate Barratt, Gerhard Kelter, Armin Maier, Markus Posch, Hongfu Lu, Xiaomin Wang, Alex Zhavoronkov, Heping Wei, Fei Huang, Daniel L. Worthley, Daniel L. Priebbenow, Siddhartha Mukherjee, Susan L. Woods, and Jonathan B. Baell
Conference Name
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 (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.
School/Discipline
Dissertation Note
Provenance
Description
Published: April 10, 2025
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Rights
© 2025 American Chemical Society