Syphers Joel L, Wright Josephine A, Liu Shen, Gee Yi Sing, Gao Fan, Mudududdla Ramesh, Che Da Qing, Chang Aeson, Sloan Erica K, Narasimhan Vignesh, Heriot Alexander, Ramsay Robert G, de Nys Rebekah, Silva Tharindie N, Vrbanac Laura, Sammour Tarik, Lawrence Matthew J, Tin Teresa, Maddern Guy J, Fenix Kevin, Kaur Harleen, Barratt Kate, Kelter Gerhard, Maier Armin, Posch Markus, Lu Hongfu, Wang Xiaomin, Zhavoronkov Alex, Wei Heping, Huang Fei, Worthley Daniel L, Priebbenow Daniel L, Mukherjee Siddhartha, Woods Susan L, Baell Jonathan B
Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia.
J Med Chem. 2025 Apr 24;68(8):8065-8090. doi: 10.1021/acs.jmedchem.4c02541. Epub 2025 Apr 10.
A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (), many of which were more selective for WEE1 over an undesirable off-target of , the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from -mutated colorectal cancer (CRC) peritoneal metastases, (IC value of 62 nM) exhibited stronger efficacy than (IC value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC value of 127 nM). Against primary CRC PDOs with -WT, significantly enhanced DNA damage, replication stress and apoptosis compared to , as well as demonstrated high selectivity over patient-matched normal healthy colon PDOs, highlighting a potential therapeutic window for cancer treatment. Overall, this investigation provides critical insight into several potent WEE1 inhibitors that exhibited exceptional efficacy against CRC PDOs and is the first to utilize a PDO platform to assess their effect on healthy and malignant cell viability.
基于已停产的前沿临床候选药物AZD1775合成了一个强效WEE1激酶抑制剂库，其中许多抑制剂对WEE1的选择性高于其不良脱靶激酶PLK1。在针对由KRAS突变的结直肠癌（CRC）腹膜转移瘤培养的患者来源类器官（PDO）进行测试时，化合物1（IC值为62 nM）比化合物2（IC值为120 nM）和同类最佳临床候选药物ZN-c3（IC值为127 nM）表现出更强的疗效。对于KRAS-WT的原发性CRC PDO，与化合物2相比，化合物1显著增强了DNA损伤、复制应激和细胞凋亡，并且对患者匹配的正常健康结肠PDO表现出高选择性，突出了癌症治疗的潜在治疗窗口。总体而言，这项研究为几种对CRC PDO表现出卓越疗效的强效WEE1抑制剂提供了关键见解，并且是首次利用PDO平台评估它们对健康和恶性细胞活力的影响。
