European journal of medicinal chemistry · 2026
Discovery of APO-50815, a potent WEE1 kinase inhibitor with exceptional efficacy against patient-derived colorectal cancer organoids.
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Syphers Joel L, Wright Josephine A, de Nys Rebekah, Silva Tharindie N, Vrbanac Laura, Barratt Kate R, Leeflang Julia, Hasan Sadia T, Thomson Sophie F, Kumar Adarsh, Krämer Andreas, Lenz Christopher, Gee Yi Sing, Chang Aeson, Young Savannah, Sloan Erica K, Knapp Stefan, Worthley Daniel L, Mukherjee Siddhartha, Stockton Kieran, Priebbenow Daniel L, Woods Susan L, Baell Jonathan B
Аннотация
Herein, we report the discovery of APO-50815 (14), a potent and selective thietane-3-ol WEE1 inhibitor. When tested against TP53-mutated colorectal cancer (CRC) patient-derived organoids (PDOs) grown from peritoneal and liver metastases, 14 exhibited outstanding anticancer efficacy, surpassing previously reported branched alkane counterpart 3, as well as clinical candidates AZD1775 (1) and ZN-c3 (2). Against primary CRC organoids with diverse TP53, BRAF and KRAS mutation profiles compared with patient-matched normal colon organoids, 14 exhibited selectively potent activity, yielding exceptionally high TI values (129-238) that highlight a substantial therapeutic window for potential cancer treatment. Against primary CRC PDOs (TP53-WT, BRAF-V600E, KRAS-WT), 14 profoundly elevated DNA damage and replication stress compared to 1, while amplifying cellular apoptosis, confirming a broadly similar but superior mode of action. Owing to its highly selective and exemplary anticancer efficacy, 14 represents a valuable tool compound for drug testing investigations against primary and metastatic CRCs, especially in the context of PDOs.