Abstract
A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.
Highlights
Cancer is a multigenetic disease with the hallmark that multiple signalling pathways aberration, which often require multiple therapeutic interventions[1,2]
We found structural optimisation based on the pyrrolo-[2,3-d] pyrimidines-2-amine scaffold could improve the inhibitory activity against the cancer cell cycle as targeting CDK4/ 6 and transcription as targeting CDK938
We found that X22 treatment significantly suppressed the phosphorylation of retinoblastoma protein (Rb) at CDK4/6 specific site Ser 780 and CDK9 specific sites Ser 807/ 811 in MCF7 and A549 cells respectively, which confirmed that X22 targeted on cyclin-dependent kinases (CDKs) (Figure 4)
Summary
Cancer is a multigenetic disease with the hallmark that multiple signalling pathways aberration, which often require multiple therapeutic interventions[1,2]. Kinases mediate various cellular activities due to their critical roles in cellular signalling, such as proliferation, apoptosis, transcription, differentiation and so on[3,4], which have been demonstrated as promising drug targets for the treatment of many diseases such as cancers[5,6,7]. Cyclin-dependent kinases (CDKs) are protein kinases involved in important cellular processes due to the complexity of their roles. They regulate the cell division, apoptosis, transcription and differentiation, which involved in a number of pathological conditions such as human cancer[11,12]. CDK9 forming heterodimeric complex with subunit cyclin T or cyclin K phosphorylates the COOH-
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