biostudies-literatureMoccia MMinistero dell'Università e della RicercaFondazione AIRC per la ricerca sul cancro ETS41770https://www.ebi.ac.uk/biostudies/studies/S-EPMC12647785biostudies-literatureUnknown15(1)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, displaScientific reportsDiscovery of a Proteolysis Targeting Chimera for TRKA and RET-derived oncoproteins.PMC12647785IG20793PRIN 2022ELYS5FWang MFederico GMoccia MSantoro MZhang LLi HYCarlomagno FWang ZfalseDiscovery of a Proteolysis Targeting Chimera for TRKA and RET-derived oncoproteins.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, displa2025-01-01T00:00:00Z2025 Nov2026-06-05T19:53:46.483Z2026-05-21T03:11:36.429ZS-EPMC126477854129073010.1038/s41598-025-25687-w