Discovery and cardioprotective effects of the first non-peptide agonists of the G protein-coupled prokineticin receptor-1

Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI) in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI

Emergence of cardio-oncology

International audienc

Prokineticin 1 receptor agonists and their uses

The present invention discloses non peptide prokineticin 1 receptor agonists and their uses for the treatment of PKRl mediated disorders, in particular for the treatment of vascular diseases, neurodegenerative diseases, diseases involving impaired gastrointestinal motility, obesity, Kallmann syndrome, normosmic hypogonadotropic hypogonadism and disturbances of circadian rhythm, and to prevent or limit the toxicity, in particular the cardiotoxicity and neurotoxicity, of drugs. The present invention also discloses a prokineticin receptor-1 agonist for use for promoting the differentiation of cardial epicardin+ progenitor cells into cardiomyocytes in a subject affected with a cardiac disease and/or the differentiation of renal epicardin+ progenitor cells into vasculogenic and/or glomerular cells in a subject affected with a renal disease. The present invention further discloses a prokineticin receptor-1 agonist for use for treating or preventing insulin resistance, in particular associated with type II diabetes

Discovery of GPCR ligands for probing signal transduction pathways

G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics (MD) simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure-based drug design (SBDD) and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand-based methods such as 3D-QSAR, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity

Flavaglines Stimulate Transient Receptor Potential Melastatin Type 6 (TRPM6) Channel Activity.

Contains fulltext : 155293.PDF (publisher's version ) (Open Access)Magnesium (Mg2+) is essential for enzymatic activity, brain function and muscle contraction. Blood Mg2+ concentrations are tightly regulated between 0.7 and 1.1 mM by Mg2+ (re)absorption in kidney and intestine. The apical entry of Mg2+ in (re)absorbing epithelial cells is mediated by the transient receptor potential melastatin type 6 (TRPM6) ion channel. Here, flavaglines are described as a novel class of stimulatory compounds for TRPM6 activity. Flavaglines are a group of natural and synthetic compounds that target the ubiquitously expressed prohibitins and thereby affect cellular signaling. By whole-cell patch clamp analyses, it was demonstrated that nanomolar concentrations of flavaglines increases TRPM6 activity by approximately 2 fold. The stimulatory effects were dependent on the presence of the alpha-kinase domain of TRPM6, but did not require its phosphotransferase activity. Interestingly, it was observed that two natural occurring TRPM6 mutants with impaired insulin-sensitivity, TRPM6-p.Val1393Ile and TRPM6-p.Lys1584Glu, are not sensitive to flavagline stimulation. In conclusion, we have identified flavaglines as potent activators of TRPM6 activity. Our results suggest that flavaglines stimulate TRPM6 via the insulin receptor signaling pathway

Discovery of iminobenzimidazole derivatives as novel cytotoxic agents

In our quest to identify inhibitors of the eukaryotic translation initiation factor 4F (eIF4F), we serendipitously discovered a novel cytotoxic agent. Even though this compound did not inhibit translation, we explored the structural requirements for its cytotoxicity due to its structural originality. A series of 1,3-disubstituted iminobenzimidazoles was synthesized and evaluated for their in vitro cytotoxicity. The structure-activity relationship studies demonstrate that hydrophobic substituent is essential for activity. The most active compounds displayed a cytotoxicity in KB, HL60 and HCT116 human cancer cells with an IC50 of about 1μM. These first-in-class series of low molecular weight synthetic molecules may provide the basis for the development of new anticancer drugs