PROTACCDK2/4/6 Degrader-2 is a PROTAC degrader specifically targeting CDK2/4/6. It can react in a single step with pivaloyl chloride to convert into the prodrug PROTACCDK2/4/6 Degrader-1. In malignant melanoma cells, this compound effectively degrades CDK2/4/6 proteins and their complexes, leading to cell cycle arrest and apoptosis, with a pronounced effect on melanoma cells. PROTACCDK2/4/6 Degrader-2 is valuable for related malignant melanoma research.

PROTAC CDK2/4/6 Degrader-2 (compound 3) exhibits significant antiproliferative effects on B16F10 and A375 cells, with an IC50 of 0.09861 μM and 0.1659 μM, respectively, after 72 hours. When used at concentrations of 0-2000 nM for 0-12 hours, it facilitates the degradation of CDK2/4/6 proteins in these cells by hijacking the E3 ubiquitin ligase CRBN, consequently attenuating activation of the downstream Rb signaling pathway. At concentrations between 50-500 nM over a period of 7 days, it maintains notable antiproliferative activity in both cell lines. Furthermore, treatment with 125-1000 nM for 48 hours induces apoptosis in a dose-dependent manner in B16F10 and A375 cells. The compound also triggers caspase-dependent apoptosis through the classical P53/Bcl-2/Bax apoptotic pathway in these cells when applied at 0-2000 nM for 48 hours. Finally, administering 25-1000 nM for 48 hours results in cell cycle arrest in A375 and B16F10 cells via degradation of cell cycle-related proteins CDK2/4/6.