Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids

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; Jonathan B. Baell

doi:10.1021/acs.jmedchem.4c02541

Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids

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 FenixHarleen 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, Jonathan B. Baell

Research output: Contribution to journal › Article › Research › peer-review

2 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	8065–8090
Number of pages	26
Journal	Journal of Medicinal Chemistry
Volume	15
Issue number	9
DOIs	https://doi.org/10.1021/acs.jmedchem.4c02541
Publication status	Published - 24 Apr 2025

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Syphers, J. L., Wright, J. A., Liu, S., Gee, Y. S., Gao, F., Mudududdla, R., Che, D. Q., Chang, A., Sloan, E. K., Narasimhan, V., Heriot, A., Ramsay, R. G., de Nys, R., Silva, T. N., Vrbanac, L., Sammour, T., Lawrence, M. J., Tin, T., Maddern, G. J., ... Baell, J. B. (2025). Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids. Journal of Medicinal Chemistry, 15(9), 8065–8090. https://doi.org/10.1021/acs.jmedchem.4c02541

@article{11bc343b110e4e36a732ba95eb6ac299,

title = "Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids",

abstract = "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.",

author = "Syphers, \{Joel L.\} and Wright, \{Josephine A.\} and Shen Liu and Gee, \{Yi Sing\} and Fan Gao and Ramesh Mudududdla and Che, \{Da Qing\} and Aeson Chang and Sloan, \{Erica K.\} and Vignesh Narasimhan and Alexander Heriot and Ramsay, \{Robert G.\} and \{de Nys\}, Rebekah and Silva, \{Tharindie N.\} and Laura Vrbanac and Tarik Sammour and Lawrence, \{Matthew J.\} and Teresa Tin and Maddern, \{Guy J.\} and Kevin Fenix and Harleen Kaur and Kate Barratt and Gerhard Kelter and Armin Maier and Markus Posch and Hongfu Lu and Xiaomin Wang and Alex Zhavoronkov and Heping Wei and Fei Huang and Worthley, \{Daniel L.\} and Priebbenow, \{Daniel L.\} and Siddhartha Mukherjee and Woods, \{Susan L.\} and Baell, \{Jonathan B.\}",

note = "Publisher Copyright: {\textcopyright} 2025 American Chemical Society.",

year = "2025",

month = apr,

day = "24",

doi = "10.1021/acs.jmedchem.4c02541",

language = "English",

volume = "15",

pages = "8065–8090",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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Syphers, JL, Wright, JA, Liu, S, Gee, YS, Gao, F, Mudududdla, R, Che, DQ, Chang, A , Sloan, EK , Narasimhan, V, Heriot, A, Ramsay, RG, de Nys, R, Silva, TN, Vrbanac, L, Sammour, T, Lawrence, MJ, Tin, T, Maddern, GJ, Fenix, K, Kaur, H, Barratt, K, Kelter, G, Maier, A, Posch, M, Lu, H, Wang, X, Zhavoronkov, A, Wei, H, Huang, F, Worthley, DL, Priebbenow, DL, Mukherjee, S, Woods, SL & Baell, JB 2025, 'Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids', Journal of Medicinal Chemistry, vol. 15, no. 9, pp. 8065–8090. https://doi.org/10.1021/acs.jmedchem.4c02541

TY - JOUR

T1 - Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids

AU - Syphers, Joel L.

AU - Wright, Josephine A.

AU - Liu, Shen

AU - Gee, Yi Sing

AU - Gao, Fan

AU - Mudududdla, Ramesh

AU - Che, Da Qing

AU - Chang, Aeson

AU - Sloan, Erica K.

AU - Narasimhan, Vignesh

AU - Heriot, Alexander

AU - Ramsay, Robert G.

AU - de Nys, Rebekah

AU - Silva, Tharindie N.

AU - Vrbanac, Laura

AU - Sammour, Tarik

AU - Lawrence, Matthew J.

AU - Tin, Teresa

AU - Maddern, Guy J.

AU - Fenix, Kevin

AU - Kaur, Harleen

AU - Barratt, Kate

AU - Kelter, Gerhard

AU - Maier, Armin

AU - Posch, Markus

AU - Lu, Hongfu

AU - Wang, Xiaomin

AU - Zhavoronkov, Alex

AU - Wei, Heping

AU - Huang, Fei

AU - Worthley, Daniel L.

AU - Priebbenow, Daniel L.

AU - Mukherjee, Siddhartha

AU - Woods, Susan L.

AU - Baell, Jonathan B.

PY - 2025/4/24

Y1 - 2025/4/24

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105002615488

U2 - 10.1021/acs.jmedchem.4c02541

DO - 10.1021/acs.jmedchem.4c02541

M3 - Article

AN - SCOPUS:105002615488

SN - 0022-2623

VL - 15

SP - 8065

EP - 8090

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 9

ER -

Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids

Abstract

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