SU 9516 is a 3-substituted indolinone that has anti-proliferative and pro-apoptotic activity in tumor cells. It is a potent inhibitor of several cyclin-dependent kinases (CDKs) with selectivity for Cdk2 (IC50s = 22, 40, and 200 nM for Cdk2/cyclin A, Cdk1/cyclin B, and Cdk4/cyclin D1). It does not inhibit PKC, p38, PDGFR, or EGFR (IC50’s = >10 μM). SU 9516 inhibits phosphorylation of the retinoblastoma protein pRb, resulting in increased pRb/E2F complex formation, cell-cycle arrest, and subsequent apoptosis. In leukemia cells (U937, Jurkat, and HL-60 cells) SU 9516 downregulates transcription of the antiapoptotic protein Mcl-1, leading to mitochondrial injury and cell death.
