Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. To date, three selective CDK4/6 inhibitors have received approval from the U.S. Food and Drug Administration (FDA), and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers. In this perspective, we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells, analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment, review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds, explain the mechanisms associated with CDK4/6 inhibitor resistance and describe solutions to overcome this issue, and briefly introduce proteolysis targeting chimera (PROTAC), a new and revolutionary technique used to degrade CDK4/6.

Expression and clinical significance of FoxO1 in idiopathic congenital talipes equinovarus in Uigur of Xinjiang / 重庆医学

Objective To investigate the expression of FoxO1 gene in idiopathic congenital talipes equinovarus(ICTEV) in Xinjiang Uigur and its correlastion with deformity degree of ICTEV.Methods The FoxO1 protein expression level of foot muscle tissues in 51 Uigur children cases of ICTEV and 25 Uigur normal children were detected by Western blot,the relative expression level of FoxO1 mRNA in different deformity degrees of ICTEV was detected by using real time fluorescence quantitative PCR.Results The Western Blot detection results showed that the expression level of FoxO1 protein in ICTEV children patients was (0.52 ± 0.03),which was lower than(1.61 ± 0.15) in normal children,the difference was statistically significant (P =0.017).The real time fluorescence quantitative PCR detection showed that the relative expression level of FoxO1 mRNA in the Dimeglio type Ⅱ,Ⅲ and Ⅳ were 1.02±0.24,0.67±0.15 and 0.24±0.19 respectively.There was negative correlation between the deformity degree of ICTEV and FoxO1 mRNA relative expression level.Conclusion The transcription level of FoxO1 gene is gradually decreased with the deformity degree aggravation of ICTEV,suggesting that the FoxO1 gene may involve in the whole onset process of Uigur ICTEV.