Discovery of APO-50815, a potent WEE1 kinase inhibitor with exceptional efficacy against patient-derived colorectal cancer organoids
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.
Authors
- Daniel L. Worthley (ORCID: https://orcid.org/0000-0003-0374-9124)
- Tharindie N. Silva (ORCID: https://orcid.org/0000-0003-2852-7704)
- Laura Vrbanac (ORCID: https://orcid.org/0009-0009-8524-7398)
- Josephine A. Wright (ORCID: https://orcid.org/0000-0002-1425-5595)
- Aeson Chang (ORCID: https://orcid.org/0000-0003-0769-516X)
- Christopher Lenz (ORCID: https://orcid.org/0009-0000-2261-2823)
- Susan L. Woods (ORCID: https://orcid.org/0000-0002-8955-2017)
- Daniel L. Priebbenow (ORCID: https://orcid.org/0000-0002-7840-0405)
- Jonathan B. Baell (ORCID: https://orcid.org/0000-0003-2114-8242)
- Yi Sing Gee (ORCID: https://orcid.org/0000-0002-2707-6270)
- Katherine Barratt
- Joel L. Syphers (ORCID: https://orcid.org/0009-0001-7139-3863)
- Adarsh Kumar (ORCID: https://orcid.org/0000-0001-5842-1324)
- Julia Leeflang (ORCID: https://orcid.org/0000-0003-1807-9143)
- S. Knapp (ORCID: https://orcid.org/0000-0002-0604-9185)
- Sophie F. Thomson
- Sadia Hasan
- Kieran Stockton
- Erica K. Sloan
- Andreas Krämer
- Savannah Young
- Rebekah de Nys
Institutions
- Goethe University Frankfurt (DE)
- Columbia University Irving Medical Center (US)
- Speech Pathology Australia (AU)
- South Australian Health and Medical Research Institute (AU)
- Molecular Research Institute (US)
- Monash University (AU)
- The University of Adelaide (AU)
- Monash Institute of Medical Research (AU)
Publication Details
- Journal
- European Journal of Medicinal Chemistry
- Published
- 2026-04-06
- DOI
- https://doi.org/10.1016/j.ejmech.2026.118838
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Gastroenterological Society of Australia
- National Health and Medical Research Council
- Structural Genomics Consortium