Targeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein
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 <b>YW-N-7</b> exhibited dual action of selectively inhibiting and depleting RET protein both <i>in vitro</i> and <i>in vivo</i>. Proteomic analysis indicated that <b>YW-N-7</b> is highly specific to RET. In cell cultures, reducing RET fusion protein potentiated the activity of LOXO-292. Furthermore, <b>YW-N-7</b> 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.
Authors
- Jianfeng Cai (ORCID: https://orcid.org/0000-0003-3106-3306)
- Vivek Subbiah (ORCID: https://orcid.org/0000-0002-6064-6837)
- Xingmin Sun (ORCID: https://orcid.org/0000-0002-8900-9161)
- Blaine H. M. Mooers (ORCID: https://orcid.org/0000-0001-8181-8987)
- Xueqing Hu (ORCID: https://orcid.org/0000-0002-6008-917X)
- Ujjwol Khatri (ORCID: https://orcid.org/0000-0002-1913-1524)
- Jie Wu (ORCID: https://orcid.org/0000-0002-3472-1717)
- Yafeng Wang (ORCID: https://orcid.org/0000-0001-9301-9736)
- Haitao Yu (ORCID: https://orcid.org/0000-0002-9745-8418)
- Shaohui Wang (ORCID: https://orcid.org/0000-0001-7764-0581)
- Tao Shen (ORCID: https://orcid.org/0009-0009-3463-8567)
- Shriya Pandey
- Ting Chao
Institutions
- Sarah Cannon Research Institute (GB)
- University of South Florida (US)
- Stephens College (US)
- Sarah Cannon (US)
- International Drug Development (FR)
- University of Oklahoma Health Sciences Center (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01424
- Citations
- 4
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases