SU9516 is a selective and potent CDK2 inhibtor with IC50 of 22 nM, less potent for CDK1/CDK4 (IC50=40/200 nM), and with no inhibition on PKC, EGFR, p38MAPK, etc.
Progression through the cell cycle is determined by sequential and specific phosphorylation events by holoenzymes involving cyclins and their catalytic partners, the CDKs. SU9516, a novel 3-substituted indolinone compound, binds to and selectively inhibits the activity of CDK2 with IC50 of 22 nM. It also inhibits CDK1 and CDK4 with IC50s of 40 nM and 200 nM. Continuous exposure to SU9516 (5 μM) for 24, 48, or 72 h resulted in a 4-52% decrease (P≤ 0.05) in CDK2-specific phosphorylation of pRb (retinoblastoma protein, a known CDK substrate) in RKO cells. The addition of 5 μM SU9516 produced a 27.6% decrease in RKO G0-G1 populations by 48 h post-drug addition and a 39.1% decrease by 72 h. A concomitant increase in RKO G2-M populations results in a G2-M block with G2-M populations increasing by 13.1% over controls at 24 h to a 34.1% at 72 h post-drug addition. After continuous exposure to 5 μM SU9516 for 24, 48, and 72 h, both RKO (10-15%) and SW480 (4-22%) cells demonstrated an increase (P ≤ 0.01) in apoptosis. With inhibition of pRb phosphorylation, proliferation in both RKO and SW480 cells decreased in a dose-dependent manner at 20 h after treatment with SU9516[3].
作用机制
SU9516’s planar structure binds to the catalytic domain of CDK2. The imidazole ring of SU9516 occupies the sugar-binding region. The N3 nitrogen on SU9516 may interact favorably with the side chain amino acid Lys89.
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