Discovery of APO-50815, a potent WEE1 kinase inhibitor with exceptional efficacy against patient-derived colorectal cancer organoids

  • Eur J Med Chem. 2026 Aug 5:312:118838. doi: 10.1016/j.ejmech.2026.118838.
Joel L Syphers  1 ,  Josephine A Wright  2 ,  Rebekah de Nys  3 ,  Tharindie N Silva  4 ,  Laura Vrbanac  5 ,  Kate R Barratt  6 ,  Julia Leeflang  7 ,  Sadia T Hasan  8 ,  Sophie F Thomson  9 ,  Adarsh Kumar  10 ,  Andreas Krämer  11 ,  Christopher Lenz  12 ,  Yi Sing Gee  13 ,  Aeson Chang  14 ,  Savannah Young  15 ,  Erica K Sloan  16 ,  Stefan Knapp  17 ,  Daniel L Worthley  18 ,  Siddhartha Mukherjee  19 ,  Kieran Stockton  20 ,  Daniel L Priebbenow  21 ,  Susan L Woods  22 ,  Jonathan B Baell  23
Affiliations
  • 1. Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 2. Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 3. Adelaide Medical School, Adelaide University, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 4. Adelaide Medical School, Adelaide University, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 5. Adelaide Medical School, Adelaide University, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 6. Adelaide Medical School, Adelaide University, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 7. Adelaide Medical School, Adelaide University, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 8. Adelaide Medical School, Adelaide University, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 9. Adelaide Medical School, Adelaide University, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 10. Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main, 60438, Germany; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, Frankfurt am Main, 60438, Germany. Electronic address: [email protected].
  • 11. Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main, 60438, Germany; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, Frankfurt am Main, 60438, Germany. Electronic address: [email protected].
  • 12. Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main, 60438, Germany; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, Frankfurt am Main, 60438, Germany. Electronic address: [email protected].
  • 13. Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 14. Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 15. Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 16. Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 17. Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main, 60438, Germany; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, Frankfurt am Main, 60438, Germany; German Translational Cancer Network (DKTK) Site Frankfurt Mainz, Heidelberg, 60590, Germany. Electronic address: [email protected].
  • 18. Colonoscopy Clinic, Spring Hill, QLD, 4000, Australia. Electronic address: [email protected].
  • 19. Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA; Manas AI, New York, NY, 10011, USA. Electronic address: [email protected].
  • 20. Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 21. Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 22. Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia; Adelaide Medical School, Adelaide University, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 23. Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia; Manas AI, New York, NY, 10011, USA. Electronic address: [email protected].
PMID: 42030708 DOI: 10.1016/j.ejmech.2026.118838
Abstract

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.

Keywords
Cancer treatment; Cell cycle checkpoint; Colorectal cancer; Metastatic colorectal cancer; Patient-derived organoids; Tool compound; WEE1 inhibitors; WEE1 kinase.
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