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Selective Macrocyclic WEE1 Kinase Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids.

Joel L Syphers·Josephine A Wright·Adarsh Kumar·Nikos To·Lewis Elson·Andreas Krämer·Susanne Müller·Viktoria Morasch·Aeson Chang·Savannah Young·Erica K Sloan·Rebekah de Nys·Tharindie N Silva·Laura Vrbanac·Kate R Barratt·Julia Leeflang·Sadia T Hasan·Robert W Gable·Stefan Knapp·Daniel L Worthley·Siddhartha Mukherjee·Kieran Stockton·Susan L Woods·Daniel L Priebbenow·Jonathan B Baell
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Abstract

Macrocyclization can enhance the selectivity of acyclic compounds toward structurally similar biological targets such as kinases. WEE1 regulates cellular homeostasis and is a promising target in oncology. The clinical candidate AZD1775 (1) failed to progress past Phase II trials because of patient tolerability issues, likely due to off-target inhibition of polo-like kinase 1 (PLK1). Herein, a computer-aided drug design approach was conducted to develop a macrocycle based on the 1-WEE1 X-ray cocrystal structure. Significantly enhanced WEE1 inhibitory selectivity over PLK1 was determined for leading macrocycle 2, which also demonstrated broader kinome-wide selectivity. Patient-derived organoids from colorectal cancer (CRC) peritoneal and liver metastases, treated with 2, demonstrated comparably strong or enhanced anticancer efficacy compared to that of 1. Against patient-matched normal colon vs primary CRC organoids, 2 potently and selectively treated CRC, as well as enhanced DNA damage compared to 1. Finally, the X-ray cocrystal structure of 2 bound to WEE1 validated its computationally predicted bioactive binding mode.

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HumansCell Cycle ProteinsProtein-Tyrosine KinasesColorectal NeoplasmsProtein Kinase InhibitorsOrganoidsAntineoplastic AgentsCrystallography, X-RayMacrocyclic CompoundsStructure-Activity RelationshipPolo-Like Kinase 1Models, MolecularPyrazolesJournal Article

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Joel L Syphers, Josephine A Wright, Adarsh Kumar, Nikos To, Lewis Elson, Andreas Krämer, Susanne Müller, Viktoria Morasch, Aeson Chang, Savannah Young, Erica K Sloan, Rebekah de Nys, Tharindie N Silva, Laura Vrbanac, Kate R Barratt, Julia Leeflang, Sadia T Hasan, Robert W Gable, Stefan Knapp, Daniel L Worthley, Siddhartha Mukherjee, Kieran Stockton, Susan L Woods, Daniel L Priebbenow, Jonathan B Baell. 2026-09-10. Selective Macrocyclic WEE1 Kinase Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids.. https://doi.org/10.1021/acs.jmedchem.6c00018

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