CG 428

CG 428 is a potent, first-in-class small molecule degrader of tropomyosin receptor kinases (TRK), specifically designed to target the intracellular kinase domain of TRK proteins. It is constructed by linking an analog of the pan-TRK inhibitor GNF-8625 to the cereblon E3 ligase ligand pomalidomide, enabling targeted protein degradation via the ubiquitin-proteasome system. CG 428 demonstrates high selectivity for TRKA over TRKC and TRKB (with Kd values of 1 nM, 4.2 nM, and 28 nM respectively) and exhibits strong anti-proliferative activity in KM12 colon cancer cells (IC50 = 2.9 nM). The compound has been studied as a topical botanical lotion intended to promote hair recovery following chemotherapy-induced alopecia and nail damage in cancer patients[1][3][4][5][8]. Its mechanism involves degrading both wild-type and fusion forms of TRKA at sub-nanomolar concentrations[3].