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