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  3. Targeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein

Targeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein

  • J Med Chem. 2025 Jan 9;68(1):81-94. doi: 10.1021/acs.jmedchem.4c01424.
Yafeng Wang 1,  Xueqing Hu 2,  Shriya Pandey 2,  Ujjwol Khatri 2,  Tao Shen 2,  Vivek Subbiah 3,  Blaine H M Mooers 2 4,  Ting Chao 1,  Shaohui Wang 5,  Huaxuan Yu 1,  Xingmin Sun 5,  Jie Wu 2,  Jianfeng Cai 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States.
  • 2 Peggy and Charles Stephenson Cancer Center and Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States.
  • 3 Early-Phase Drug Development, Sarah Cannon Research Institute, Nashville, Tennessee 37203, United States.
  • 4 Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States.
  • 5 Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
PMID: 39723919 DOI: 10.1021/acs.jmedchem.4c01424
Abstract

The rearranged-during-transfection (RET) kinase is a validated target for the treatment of RET-altered cancers. Currently approved RET-selective kinase inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), increase the oncogenic RET protein level upon treatment, which may affect their efficacy. We seek to reduce the oncogenic RET protein level and RET kinase activity simultaneously. Here, we report the development of proteolysis targeting chimera (PROTAC) degraders of oncogenic RET protein. Compound YW-N-7 exhibited dual action of selectively inhibiting and depleting RET protein both in vitro and in vivo. Proteomic analysis indicated that YW-N-7 is highly specific to RET. In cell cultures, reducing RET fusion protein potentiated the activity of LOXO-292. Furthermore, YW-N-7 showed significant activity in inhibiting KIF5B-RET-driven xenograft tumors in Animals. This study exemplifies the feasibility of simultaneously inhibiting and degrading oncogenic RET kinase for Cancer therapy.

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