Discovery of novel CDK2 inhibitors using multistage virtual screening and in vitro melanoma cell lines

Cyclin‐dependent kinases 2 (CDK2) is a serine/threonine‐protein kinase, which plays a key role in the regulation of cell cycle and is related to the occurrence and development of melanoma. In this study, we identified potent inhibitors for CDK2 by combining a multistage virtual screening strategy with bioassay validations. The biochemical activity of compounds was validated with ADP‐Glo™ Kinase assay in vitro, and the results indicated that the biochemical activity of compound 1 (C1) was better than other selected compounds. Cell viability assay showed that the minimum inhibition concentration of C1 for CDK2 was lower than 4 μM. Further functional test results showed that C1 exerted significant antiproliferative, pro‐apoptosis, and anti‐migration activity in melanoma cell lines (A375 cells, WM35 cells, and A875 cells). Our findings suggested that the C1, virtually screened from compound libraries, as the novel inhibitor of CDK2, may be further developed as an effective therapeutic agent in the treatment of melanoma lines. Active compounds targeting CDK2 protein obtained from compound libraries containing more than 3 million compounds via multistage virtual screening strategy. The western blotting assay indicated that compound 1 could inhibit the activities of CDK2/CyclinA and CDK2/CyclinE complex. Moreover, compound 1 exerted significant antiproliferative, pro‐apoptosis, and anti‐migration activity in melanoma cell lines.