Targeting Akt/PKB in pediatric tumors: A review from preclinical to clinical trials.

The serine/threonine kinase Akt is a major player in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and its modulation impacts multiple cellular processes such as growth, proliferation, and survival. Several abnormalities in this pathway have been documented over the years, and these alterations were shown to have great implications in tumorigenesis and resistance to chemotherapy. Thus, multiple Akt inhibitors have been developed and tested in adult tumors, and some of them are currently undergoing phase I, II, and III clinical trials for distinct cancers that arise during adulthood. Despite that, the impact of these inhibitors is still not fully understood in pediatric tumors, and Akt-specific targeting seems to be a promising approach to treat children affected by cancers. This review summarizes recent available evidence of Akt inhibitors in pediatric cancers, from both preclinical and clinical studies. In short, we demonstrate the impact that Akt inhibition provides in tumorigenesis, and we suggest targeting the PI3K/Akt/mTOR signaling pathway, alone or in combination with other inhibitors, is a feasible tool to achieve better outcomes in pediatric tumors.

Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors.

The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, respectively. Among the known inhibitors for these proteases, we have described N4-benzyl-N2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as a competitive cruzain inhibitor (Ki = 1.4 µM). Here, we describe the synthesis and biological evaluation of 22 analogs of 1a, containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring. The analogs demonstrate low micromolar inhibition of the target proteases and cidal activity against Trypanosoma cruzi with up to two log selectivity indices in counterscreens with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations. During the optimization of 1a, structure-based design and prediction of physicochemical properties were employed to maintain potency against the enzymes while removing colloidal aggregator characteristics observed for some molecules in this series.

Synthesis and structure-activity relationship studies of cruzain and rhodesain inhibitors.

Chagas disease and Human African trypanosomiasis (HAT) are important public health issues in Latin American and sub-Saharan African countries, respectively, and are responsible for a significant number of deaths. The drugs currently used to treat Chagas disease and HAT present efficacy, toxicity, and/or resistance issues; thus, there is a clear need for the discovery of novel targets and drug candidates to combat these diseases. In recent years, much effort has been made to find inhibitors of cruzain and rhodesain, which are promising targets for the design of novel trypanocidal compounds, since they are essential for parasite survival. Many reviews covering the design of novel cruzain and rhodesain inhibitors have been published; however, none have focused on the chemistry of the inhibitors. Thus, in the present work we reviewed the synthetic strategies and routes for the preparation of relevant classes of cruzain and rhodesain inhibitors. Perhaps the most important are the vinyl sulfone derivatives, and a very efficient synthetic strategy based on the Horner-Wadsworth-Emmons reaction was developed to yield these compounds. Modern approaches such as the asymmetric addition of substituted ethynyllithium to N-sulfinyl ketimines were used to produce the chiral alkynes that were employed in the preparation of important chiral triazole derivatives (potent cruzain inhibitors) and chiral HPLC resolution was used for the preparation of enantiopure 3-bromoisoxazoline derivatives (rhodesain inhibitors). Moreover, we also highlight the most important activity results and updated SAR results.