Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations

Chuan Zhou; Zisheng Fan; Zehui Zhou; Yupeng Li; Rongrong Cui; Chaoyi Liu; Guizhen Zhou; Xingxing Diao; Hualiang Jiang; Mingyue Zheng; Sulin Zhang; Tianfeng Xu

doi:10.1021/acs.jmedchem.1c01774

Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations

Chuan Zhou
, Zisheng Fan
, Zehui Zhou
, Yupeng Li
, Rongrong Cui
, Chaoyi Liu
, Guizhen Zhou
, Xingxing Diao
, Hualiang Jiang
, Mingyue Zheng
, Sulin Zhang
, Tianfeng Xu

Carcinogenesis and Chemoprevention

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

74 Scopus citations

Abstract

Regulating SOS1 functions may result in targeted pan-KRAS therapies. Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies. SOS1 agonists provide new opportunities to treat cancer; however, the underlying mechanisms still warrant investigation. We here report the discovery of the first SOS1 PROTACs designed uniquely by connecting a VHL ligand to the reported SOS1 agonist, ensuring that the observed inhibitory activity results from degraders. The best compound 9d induced SOS1 degradation in various KRAS-driven cancer cells and displayed superior antiproliferation activity compared to the agonist itself. Tumor xenograft study clearly showed the promising antitumor potency of 9d against human lung cancer. This study provides good evidence of using agonists to design SOS1 PROTACs and demonstrates that targeted SOS1 degradation represents an effective therapeutic strategy for overcoming KRAS-driven cancers.

Original language	English (US)
Pages (from-to)	3923-3942
Number of pages	20
Journal	Journal of medicinal chemistry
Volume	65
Issue number	5
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01774
State	Published - Mar 10 2022

Bibliographical note

Funding Information:
The authors would like to thank the Natural Science Foundation of Shanghai (no. 20ZR1468500 to T.X.), the Shanghai Pujiang Program (no. 19PJ1411400 to T.X.), the National Natural Science Foundation of China (81903639 to S.Z.), the Lingang Laboratory (LG202102-01-02 to M.Z.), the Shanghai Municipal Science and Technology Major Project, Shanghai Sailing Program (no. 19YF1457800 to S.Z.), and the China Postdoctoral Science Foundation (2021M693270 to C.Z.) for their financial support.

Publisher Copyright:
© 2022 American Chemical Society.

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SDG 3 Good Health and Well-being

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10.1021/acs.jmedchem.1c01774

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title = "Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations",

abstract = "Regulating SOS1 functions may result in targeted pan-KRAS therapies. Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies. SOS1 agonists provide new opportunities to treat cancer; however, the underlying mechanisms still warrant investigation. We here report the discovery of the first SOS1 PROTACs designed uniquely by connecting a VHL ligand to the reported SOS1 agonist, ensuring that the observed inhibitory activity results from degraders. The best compound 9d induced SOS1 degradation in various KRAS-driven cancer cells and displayed superior antiproliferation activity compared to the agonist itself. Tumor xenograft study clearly showed the promising antitumor potency of 9d against human lung cancer. This study provides good evidence of using agonists to design SOS1 PROTACs and demonstrates that targeted SOS1 degradation represents an effective therapeutic strategy for overcoming KRAS-driven cancers.",

author = "Chuan Zhou and Zisheng Fan and Zehui Zhou and Yupeng Li and Rongrong Cui and Chaoyi Liu and Guizhen Zhou and Xingxing Diao and Hualiang Jiang and Mingyue Zheng and Sulin Zhang and Tianfeng Xu",

note = "Funding Information: The authors would like to thank the Natural Science Foundation of Shanghai (no. 20ZR1468500 to T.X.), the Shanghai Pujiang Program (no. 19PJ1411400 to T.X.), the National Natural Science Foundation of China (81903639 to S.Z.), the Lingang Laboratory (LG202102-01-02 to M.Z.), the Shanghai Municipal Science and Technology Major Project, Shanghai Sailing Program (no. 19YF1457800 to S.Z.), and the China Postdoctoral Science Foundation (2021M693270 to C.Z.) for their financial support. Publisher Copyright: {\textcopyright} 2022 American Chemical Society.",

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AU - Zhou, Chuan

AU - Fan, Zisheng

AU - Zhou, Zehui

AU - Li, Yupeng

AU - Cui, Rongrong

AU - Liu, Chaoyi

AU - Zhou, Guizhen

AU - Diao, Xingxing

AU - Jiang, Hualiang

AU - Zheng, Mingyue

AU - Zhang, Sulin

AU - Xu, Tianfeng

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PY - 2022/3/10

Y1 - 2022/3/10

N2 - Regulating SOS1 functions may result in targeted pan-KRAS therapies. Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies. SOS1 agonists provide new opportunities to treat cancer; however, the underlying mechanisms still warrant investigation. We here report the discovery of the first SOS1 PROTACs designed uniquely by connecting a VHL ligand to the reported SOS1 agonist, ensuring that the observed inhibitory activity results from degraders. The best compound 9d induced SOS1 degradation in various KRAS-driven cancer cells and displayed superior antiproliferation activity compared to the agonist itself. Tumor xenograft study clearly showed the promising antitumor potency of 9d against human lung cancer. This study provides good evidence of using agonists to design SOS1 PROTACs and demonstrates that targeted SOS1 degradation represents an effective therapeutic strategy for overcoming KRAS-driven cancers.

AB - Regulating SOS1 functions may result in targeted pan-KRAS therapies. Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies. SOS1 agonists provide new opportunities to treat cancer; however, the underlying mechanisms still warrant investigation. We here report the discovery of the first SOS1 PROTACs designed uniquely by connecting a VHL ligand to the reported SOS1 agonist, ensuring that the observed inhibitory activity results from degraders. The best compound 9d induced SOS1 degradation in various KRAS-driven cancer cells and displayed superior antiproliferation activity compared to the agonist itself. Tumor xenograft study clearly showed the promising antitumor potency of 9d against human lung cancer. This study provides good evidence of using agonists to design SOS1 PROTACs and demonstrates that targeted SOS1 degradation represents an effective therapeutic strategy for overcoming KRAS-driven cancers.

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Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations

Abstract

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