UCB-101333-3

Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, 31 (YL93) was structure-based designed and synthesized, which had MDM2/4 binding K_i values of 1.1 and 642 nM, respectively. In three MDM4-overexpressing cancer cell lines harboring wild-type p53, 31 shows improved cell growth inhibition activities compared to RG7388, an MDM2-selective inhibitor in late-stage clinical trials. Mechanistic studies show that 31 increased cellular protein levels of p53 and p21 and upregulated the expression of p53-targeted genes in RKO cells with MDM4 amplification. In addition, 31 induced cell-cycle arrest and apoptosis in western blot and flow cytometry assays. Taken together, dual inhibition of MDM2/4 by 31 elicited stronger antitumor activities in vitro compared to selective MDM2 inhibitors in wild-type p53 and MDM4-overexpressing cancer cells.

PDE inhibitors could be useful in the treatment of asthma because of their bronchodilator and/or anti-inflammatory activities. Recently, some selective PDE3, PDE4 and PDE3/4 inhibitors have been shown to have beneficial effects in patients with asthma suggesting that such drugs may offer novel therapeutic options for the treatment of this disease.

The authors describe the main PDE families that could be involved in asthma as well as the PDE inhibitors that have been evaluated for the treatment of asthma.

Although the potential therapeutic utility of PDE inhibitors has been demonstrated in various animal models of asthma, their clinical efficacy have been restricted by the dose-limiting side effects; no PDE inhibitor has yet been approved for the treatment of patients with asthma. Although new PDE inhibitors have been synthesised, most data are from cellular and tissue-level studies with human trials still on the horizon. Apparently, only CHF 6001, an inhaled PDE4 inhibitor, and RPL554, a dual PDE3/4 inhibitor, are still under clinical development. Further data from these new drugs are eagerly anticipated to better understand where these drugs might stand in the future treatment of asthma.