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

We
report compounds 5 (CG416) and 6 (CG428)
as two first-in-class tropomyosin receptor kinase (TRK) degraders
that target the intracellular kinase domain of TRK. Degraders 5 and 6 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 6, 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 5 is highly selective
for the intended target. TPM3-TRKA protein degradation induced by 5 and 6 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 5 and 6 showed good plasma exposure levels in
mice. Therefore, 5 and 6 are valuable chemical
tool compounds for investigating the in vivo function
of TRK fusion during tumorigenesis. Our study also paves the way for
pharmacological degradation of TRK.