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 Baell
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.