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. BaellAbstract
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.