Ro 3306 is a potent and selective inhibitor of CDK1 with Ki value of 35 nM for CDK1/cyclin B1, 10-fold selectivity relative to CDK2/cyclin E and > 50-fold relative to CDK4/cyclin D.
The CDKs (cyclin dependent kinases), as direct regulators of specific phases of the cell cycle, can control cellular proliferation and transcription with their activating cyclin partners and subunit inhibitors. CDK1, through forming complex with Cyclin A or B can trigger S-G2 and G2 to M transitions and G2 progression. RO-3306 is a selective CDK1 inhibitor with Ki value of 20nM (by the IMAP assay). Ro 3306 can reversibly arrest human cells at the G2/M border of the cell cycle and allows for effective cell synchronization in early mitosis. Treatment with 9uM RO-3306 for 20h caused significant decreased protein level of Cyclin E after 8h release from the nocodazole block, as well as Cyclin A and Cyclin B1 after 12h release from the nocodazole block, in HeLa cells synchronized in mitosis by a shake-off after 14 h of incubation in 100nM nocodazole (Cell transition through the G1 and S phase), without significantly affect cellular CDK2 and CDK4 function. HeLa cells traversed normally through the S phase in the presence of 9uM RO-3306 and effectively accumulated in the G2/M phase. Inhibition of CDK1 activity by 9uM RO-3306 forced HeLa cells in prometaphase to exit mitosis without cell division as indicated by the rapid disappearance of phosphohistone-H3 and chromatin decondensation, as well as rapid transition of Mcm2 from the soluble fraction to chromatin. Compared with MCF10A and MCF12A cells, treatement with 9 uM RO-3306 induced larger proapoptotic fraction, which showed that RO-3306 appeared to be more proapoptotic in cancer cells and may have utility as anticancer agents[1]. Combinatorial treatment RO3306 4mg/kg plus sorafenib 30mg/kg could suppress the tumor growth in hepatocellular carcinoma PDX models[2].
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