A growing number of reports suggested that the inhibitor targeting cyclin-dependent kinases (CDK) 2/4/6 can act as a more feasible chemotherapy strategy. In the present paper, a novel PROTAC molecule was developed based on the structure of Ribociclib’s derivative. In malignant melanoma cells, the degrader can not only degrade CDK 2/4/6 simultaneously and effectively, but also remarkably induce cell cycle arrest and apoptosis of melanoma cells. Moreover, PROTAC molecules with CRBN ligands always have poor oral bioavailability. We developed the orally bioavailable prodrug for the first time. It would provide general solution for oral administration of the PROTAC molecules, derived from CRBN ligands, for animal test conveniently. Display omitted •Compound 3 is an efficient PROTAC molecule which can degrade CDK 2/4/6 simultaneously and effectively.•Compound 3 Remarkably inhibit the growth of melanoma cells.•The first orally bioavailable prodrug was developed for the PROTAC molecules with CRBN ligands.•The oral bioavailability of compound 11 is up to 68%.