X22(Wenzhou Medical University)

Diabetic kidney disease (DKD) is considered a chronic inflammatory renal disease induced by hyperglycemia. Therefore, even meticulous control of blood glucose levels cannot prevent the progression of DKD efficiently. Management of the inflammatory response could be one of the most promising strategies for treatment. We previously validated an imidazopyridine derivative (X22) as an active compound in suppressing lipopolysaccharide-induced inflammation. However, its potential for protection against DKD has not been exanimated. In the present study, streptozotocin-induced type 1 diabetic mice were used to study the effect of X22 on DKD associated inflammation and fibrosis by Q-PCR and immunoblotting assays. The results showed that X22 significantly inhibited the production of inflammatory cytokines (IL-6, TNF-α) and fibrosis biomarkers. At the same time, kidney function was dramatically improved. To elucidate the mechanism of action of X22, we examined its effects on the NRK-52E cell line. Strikingly, X22 restored the protein level of IKB-α and blocked the nuclear translocation of P65. Collectively, the data indicate that X22 can attenuate diabetic kidney dysfunction and inflammatory injury and may represent a potential agent for the treatment of DKD. It could be a potential agent for use in the treatment of DKD.

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.