CDK4/6, forming a complex with its partner Cyclin D1/2/3, can mediate the phosphorylation of Rb in G1 cell cycle, as well as stimulating the synthesis cyclin E and D-type cyclins controlled by extracellular mitogens[2]. Dinaciclib can inhibit CDK2, CDK5, CDK1, and CDK9 activity with IC50 values of 1, 1, 3 and 4 nM (measured by Recombinant cyclin/CDK), respectively. Dinaciclib strongly suppressed phosphorylation of Rb on Ser 807/811 at concentrations >6.25 nM for 16h in A2780 cells. Along with that, apoptosis as indicated by the appearance of the p85 PARP cleavage can also be observed. Dinaciclib has broad antiproliferative activity against a wide range of tumor cells, including prostate, breast, colon, SCLC, SCLC, ovarian, pancreatic, melanoma, leukemia, bladder, liver, mantle and lymphoma cell lines, with IC50 ranging from 6-17 nM. Exposure to 250-500 nM of dinaciclib is sufficient to completely suppress DNA synthesis for 24 hours in A2780 cells and that was correlated with the accumulation of apoptosis (sub-G1), which means that short exposures to dinaciclib can induce long-lasting effects in target cells. Intraperitoneal administration of dinaciclib at 8, 16, 32 and 48 mg/kg daily for 10 days resulted in tumor inhibition by 70%, 70%, 89%, and 96%, respectively, in A2780 xenograft mice[1]. Up to now, a lot of clinical trails of dinaciclib treatment for cancer, including ALL, AML, CLL, mantle cell lymphoma, multiple myeloma, melanoma, NSCLC, breast and pancreatic cancer, are undergoing.
作用机制
Dinaciclib can interact with both ATP-binding site and the acetyl-lysine recognition site of bromodomains of CDKs[3].
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