Discovery of First-In-Class Potent and Selective Tropomyosin Receptor Kinase Degraders.

We report compounds (CG416) and (CG428) as two first-in-class tropomyosin receptor kinase (TRK) degraders that target the intracellular kinase domain of TRK. Degraders and reduced levels of the tropomyosin 3 (TPM3)-TRKA fusion protein in KM12 colorectal carcinoma cells and inhibited downstream PLCγ1 signaling at sub-nanomolar concentrations. Both degraders also degraded human wild-type TRKA with similar potency. Interestingly, both degraders, especially , showed selectivity for the degradation of endogenous TPM3-TRKA over ectopically expressed ATP/GTP binding protein-like 4 (AGBL4)-TRKB or ETS variant transcription factor 6 (ETV6)-TRKC fusion proteins in KM12 cells. Global proteomic profiling assays demonstrated that is highly selective for the intended target. TPM3-TRKA protein degradation induced by and was further confirmed to be mediated through cereblon and the ubiquitin-proteasome system. Compared with the parental TRK kinase inhibitor, both degraders exhibited higher potency for inhibiting growth of KM12 cells. Moreover, both and showed good plasma exposure levels in mice. Therefore, and are valuable chemical tool compounds for investigating the function of TRK fusion during tumorigenesis. Our study also paves the way for pharmacological degradation of TRK.