Discovery of a Proteolysis Targeting Chimera for TRKA and RET-derived oncoproteins.

ABSTRACT: We designed Proteolysis Targeting Chimeras (PROTACs) to target Tropomyosin Receptor Kinase A (TRKA) and Rearranged during Transfection (RET) oncogenic proteins. We analyzed a series of 22 PROTACs, based on the RET and TRKA small molecule inhibitor Pz-1 and ligands of E3 ligase complex component Cereblon (CRBN). The compounds were tested in TPC-1 and KM12 cells, derived from papillary thyroid carcinoma and colorectal carcinoma, and harboring the CCDC6-RET and TPM3-TRKA oncoproteins, respectively. We identified several RET and TPM3-TRKA PROTACs, able to induce their degradation. Consistently, one of the most active degraders, compound 9, exhibited a strong anti-proliferative effect in several cancer cell lines derived from human medullary and papillary thyroid, lung and colon cancers, displa

SUBMITTER: Moccia M 

PROVIDER: S-EPMC12647785 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature