PDE4B inhibitors(Yishi Pharmaceutical)

Phosphodiesterase 4B (PDE4B) is a crucial enzyme in the phosphodiesterases (PDEs), acting as a regulator of cyclic adenosine monophosphate (cAMP). It is involved in cancer process through PDE4B/cAMP signaling pathway. Cancer occurs and develops with the regulation of PDE4B in the body, suggesting that PDE4B is a promising therapeutic target.

This review covereed the function and mechanism of PDE4B in cancer. We summarized the possible clinical applications of PDE4B, and highlighted the possible ways to develop clinical applications of PDE4B inhibitors. We also discussed some common PDEs inhibitors, and expected the development of combined targeting PDE4B and other PDEs drugs in the future.

The existing research and clinical data can strongly prove the role of PDE4B in cancer. PDE4B inhibition can effectively increase cell apoptosis, inhibit cell proliferation, transformation, migration, etc., indicating that PDE4B inhibition can effectively inhibit the development of cancer. Other PDEs may antagonize or coordinate this effect. As for the further study on the relationship between PDE4B and other PDEs in cancer, it is still a challenge to develop multi-targeted PDEs inhibitors.

Tardive dyskinesia (TD) is an involuntary movement disorder that occurs in ∼20% of patients after extended antipsychotic use. Its pathophysiology is unclear; however, familial patterns and gene association studies indicate an inherited component to risk. The disrupted in schizophrenia 1 (DISC1) gene was selected for analysis because it interacts with and regulates two important proteins involved in antipsychotic medication action: the dopamine D2 receptor and the cAMP phosphodiesterase type IVB (PDE4B). The D2 receptor is the obligate target of all existing antipsychotic medications, and PDE4B hydrolyzes cAMP, a core signaling molecule activated by agonist binding to the D2 receptor. Notably, PDE4B inhibitors such as rolipram have been shown to reduce TD-like behaviours in animal models. Nine single-nucleotide polymorphisms (SNPs) in the DISC1 gene were investigated in a sample of 193 chronic schizophrenia patients for association with the presence and severity of TD, with age and sex as additional variables. TD severity was measured using the Abnormal Involuntary Movement Scale (AIMS). Two DISC1 SNPs were associated with TD severity (uncorrected p < 0.05), but these findings did not survive correction for multiple testing. This preliminary investigation suggests that DISC1 gene variants do not affect risk for TD or severity.