2. Academic Validation
  3. Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations

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

  • J Med Chem. 2022 Mar 10;65(5):3923-3942. doi: 10.1021/acs.jmedchem.1c01774.
Chuan Zhou 1,  Zisheng Fan 2 3,  Zehui Zhou 1 4,  Yupeng Li 5,  Rongrong Cui 2 3,  Chaoyi Liu 1,  Guizhen Zhou 2 3,  Xingxing Diao 6,  Hualiang Jiang 2 3 4 7,  Mingyue Zheng 2 3 4 7,  Sulin Zhang 3 4,  Tianfeng Xu 1 4 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 5 Masonic Cancer Center & Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
  • 6 Shanghai Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 7 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 35230841 DOI: 10.1021/acs.jmedchem.1c01774
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.

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