2412055-93-5

CG428 is a tropomyosin receptor kinase (TRK) degrader that targets the intracellular kinase domain of TRK. CG428 reduced levels of the tropomyosin 3 (TPM3)-TRKA fusion protein in KM12 colorectal carcinoma cells and inhibited downstream PLCγ1 signaling at sub-nanomolar concentrations. CG428 also degraded human wild-type TRKA.

CG428 is a potent and selective tropomyosin receptor kinase (TRK) PROTAC degrader that has anti-tumor activity. CG428 reduces levels of the tropomyosin 3 (TPM3)-TRKA fusion protein in KM12 colorectal carcinoma cells (DC50 = 0.36 nM) and inhibits downstream PLCγ1phosphorylation (IC50 = 0.33 nM). CG428 has a higher binding affinity for TRKA than TRKB and TRKC (Kd = 1 nM, 28 nM and 4.2 nM, respectively). In addition, CG428 effectively inhibits KM12 cell growth (IC50 = 2.9 nM)[1].(Pink: TRK inhibitor (HY-118271); Black: linker (HY-W067489); Blue: CRBN Ligand (HY-41547))

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[1] Chen L, et al. Discovery of First-In-Class Potent and Selective Tropomyosin Receptor Kinase Degraders. J Med Chem. 2020 Dec 10;63(23):14562-14575. DOI:10.1021/acs.jmedchem.0c01342