Joel L. Syphers, Josephine A. Wright, Shen Liu, Yi Sing Gee, Fan Gao, Ramesh Mudududdla, Da Qing Che, Aeson Chang, Erica K. Sloan, Vignesh Narasimhan, Alexander Heriot, Robert G. Ramsay, Rebekah de Nys, Tharindie N. Silva, Laura Vrbanac, Tarik Sammour, Matthew J. Lawrence, Teresa Tin, Guy J. Maddern, Kevin Fenix, Harleen Kaur, Kate Barratt, Gerhard Kelter, Armin Maier, Markus Posch, Hongfu Lu, Xiaomin Wang, Alex Zhavoronkov, Heping Wei, Fei Huang, Daniel L. Worthley, Daniel L. Priebbenow, Siddhartha Mukherjee*, Susan L. Woods* and Jonathan B. Baell*,
{"title":"WEE1激酶抑制剂对患者来源的转移性结直肠癌类器官具有有效活性的发现","authors":"Joel L. Syphers, Josephine A. Wright, Shen Liu, Yi Sing Gee, Fan Gao, Ramesh Mudududdla, Da Qing Che, Aeson Chang, Erica K. Sloan, Vignesh Narasimhan, Alexander Heriot, Robert G. Ramsay, Rebekah de Nys, Tharindie N. Silva, Laura Vrbanac, Tarik Sammour, Matthew J. Lawrence, Teresa Tin, Guy J. Maddern, Kevin Fenix, Harleen Kaur, Kate Barratt, Gerhard Kelter, Armin Maier, Markus Posch, Hongfu Lu, Xiaomin Wang, Alex Zhavoronkov, Heping Wei, Fei Huang, Daniel L. Worthley, Daniel L. Priebbenow, Siddhartha Mukherjee*, Susan L. Woods* and Jonathan B. Baell*, ","doi":"10.1021/acs.jmedchem.4c0254110.1021/acs.jmedchem.4c02541","DOIUrl":null,"url":null,"abstract":"<p >A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (<b>1</b>), many of which were more selective for WEE1 over an undesirable off-target of <b>1</b>, the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from <i>TP53</i>-mutated colorectal cancer (CRC) peritoneal metastases, <b>34</b> (IC<sub>50</sub> value of 62 nM) exhibited stronger efficacy than <b>1</b> (IC<sub>50</sub> value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC<sub>50</sub> value of 127 nM). Against primary CRC PDOs with <i>TP53</i>-WT, <b>34</b> significantly enhanced DNA damage, replication stress and apoptosis compared to <b>1</b>, 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.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 8","pages":"8065–8090 8065–8090"},"PeriodicalIF":6.8000,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids\",\"authors\":\"Joel L. Syphers, Josephine A. Wright, Shen Liu, Yi Sing Gee, Fan Gao, Ramesh Mudududdla, Da Qing Che, Aeson Chang, Erica K. Sloan, Vignesh Narasimhan, Alexander Heriot, Robert G. Ramsay, Rebekah de Nys, Tharindie N. Silva, Laura Vrbanac, Tarik Sammour, Matthew J. Lawrence, Teresa Tin, Guy J. Maddern, Kevin Fenix, Harleen Kaur, Kate Barratt, Gerhard Kelter, Armin Maier, Markus Posch, Hongfu Lu, Xiaomin Wang, Alex Zhavoronkov, Heping Wei, Fei Huang, Daniel L. Worthley, Daniel L. Priebbenow, Siddhartha Mukherjee*, Susan L. Woods* and Jonathan B. Baell*, \",\"doi\":\"10.1021/acs.jmedchem.4c0254110.1021/acs.jmedchem.4c02541\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (<b>1</b>), many of which were more selective for WEE1 over an undesirable off-target of <b>1</b>, the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from <i>TP53</i>-mutated colorectal cancer (CRC) peritoneal metastases, <b>34</b> (IC<sub>50</sub> value of 62 nM) exhibited stronger efficacy than <b>1</b> (IC<sub>50</sub> value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC<sub>50</sub> value of 127 nM). 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Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids
A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (1), many of which were more selective for WEE1 over an undesirable off-target of 1, the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from TP53-mutated colorectal cancer (CRC) peritoneal metastases, 34 (IC50 value of 62 nM) exhibited stronger efficacy than 1 (IC50 value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC50 value of 127 nM). Against primary CRC PDOs with TP53-WT, 34 significantly enhanced DNA damage, replication stress and apoptosis compared to 1, 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.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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