| CYC202 is a potent inhibitor of recombinant cyclin dependent kinase (CDK)-2/cyclin E kinase. CYC202 inhibits CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, CDK4/cyclin D1, CDK7/cyclin H and extracellar-signal regulated kinase (ERK)-2with IC50s of 2.69, 0.71, 0.10, 14.21, 0.49 and 1.17 µM, respectively. [1] Treatment of HT29 and KM12 colon carcinoma cell lines with CYC202 decreases both retinoblastoma protein phosphorylation and total retinoblastoma protein. CYC202 causes a clear reduction in cyclins D1, A, and B1 mRNA, whereas c-FOS mRNA increases by 2-fold. CYC202 also inhibits transcription, possibly via inhibition of CDK7 and CDK9 complexes and CYC202 has the potential to inhibit CDK4 and CDK1 activities in cancer cells through the down-regulation of the corresponding cyclin partners. CYC202 has been shown to cause both G1 and G2-M arrest in the non-small cell lung carcinoma cell line MR65 and also in the neuroblastoma line CHP-212, consistent with inhibition of CDK1 and CDK2. CYC202 is 7-fold more potent at inhibiting CDK2/cyclin E with an IC50 of 100 nM, nearly 2-fold more potent against CDK2/cyclin A with an IC50 of 540 nM, and 4-fold less potent against CDK1/cyclin B with an IC50 of 12.69 μM. CYC202 also inhibits CDK7/cyclin H with an IC50 of 490 nM. CYC202 not only inhibits RB phosphorylation but also induces activation of the MAPK pathway, leading to positive regulation of downstream transcription factors, ELK-1 and c-FOS. CYC202 causes a decrease in the expression of cyclins D1, A, and B1, possibly through the loss of total and phosphorylated RNA polymerase II. [2] In vitro, CYC202 has a cytotoxic effect across a range of different human tumour types. CYC202 is least efficacious against the Chago-K1 and NCI-H69 lung carcinoma cell lines, and most potent against LoVo and MESSA/DX5 cells??ith the average cytotoxic IC50 of 15.2 µM. CYC202 has a greater potency against p53 wild-type cells with an average IC50 of 12.0 µM than against p53 mutant cell lines with an average IC50 of 18.2 µM. CYC202 induces cell death that is not reliant on prior arrest of cell growth at any specific check point. In vivo, in the MESSA-DX5 xenograft model, treatment with CYC202 at 500 mg/kg slows the growth rate of the Messa DX5 tumours, resulting in a tumour growth delay of 4 times the start volume compared to vehicle treated control tumours of 7.5 days. The tumour volumes of mice treated with CYC202 at 500 mg/kg are significantly smaller compared to the control tumours on days 4, 7 and 11, the only days that the vehicle group is available for comparison. The overall effect of CYC202 at either dose therefore is to cause a reduction in the rate of growth of this rapidly growing uterine tumour xenograft. [1] |
