Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism.

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems.

GDPRValidator: a tool to enable companies using cloud services to be GDPR compliant.

This article presents a tool called GDPRValidator that aims to assist small and medium-sized enterprises (SMEs) that have migrated their services, or a part of them, to the cloud to be General Data Protection Regulation (GDPR) compliant when they manage and store employees' or customers' data in the cloud. As these companies have a limited budget to hire legal experts to guide them in complying with GDPR, the main objective of this tool is to help SMEs to be more competitive by saving a considerable amount of money. By using GDPRValidator, these companies can learn and begin the GDPR compliance process by themselves and decide whether it will be necessary to hire GDPR legal experts in the end.

Current Approaches for Predicting Human PK for Small Molecule Development Candidates: Findings from the IQ Human PK Prediction Working Group Survey.

Accurate prediction of human clearance (CL) and volume of distribution at steady state (V) for small molecule drug candidates is an essential component of assessing likely efficacious dose and clinical safety margins. In 2021, the IQ Consortium Human PK Prediction Working Group undertook a survey of IQ member companies to understand the current PK prediction methods being used to estimate these parameters across the pharmaceutical industry. The survey revealed a heterogeneity in approaches being used across the industry (e.

Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors.

The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(±mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2-]pyrimidine derivative as a moderate dual PI3K/PIM-1 inhibitor.

Omipalisib inspired macrocycles as dual PI3K/mTOR inhibitors.

Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells. Compounds targeting this pathway are under active development as anticancer therapeutics and some of them have reached advanced clinical trials or been approved by the FDA. Dual PI3K/mTOR inhibitors combine multiple therapeutic efficacies in a single molecule by inhibiting the pathway both upstream and downstream of AKT.

Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.

Visceral leishmaniasis (VL), caused by the protozoan parasites and , is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease.

Discovery of novel triazolo[4,3-b]pyridazin-3-yl-quinoline derivatives as PIM inhibitors.

PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2).

Comparing the influence of two immunosuppressants (fingolimod, azathioprine) on wound healing in a rat model of primary and secondary intention wound closure.

In this study, rat models of wound closure by first and second intention were developed to evaluate the influence that two immunosuppressants for treating multiple sclerosis (fingolimod, azathioprine) have on wound healing. Sixty-three Sprague-Dawley rats were daily treated with fingolimod (0.6 mg/kg), azathioprine (2.

Identification of novel PI3K inhibitors through a scaffold hopping strategy.

A scaffold hopping strategy, including intellectual property availability assessment, was successfully applied for the discovery of novel PI3K inhibitors. Compounds were designed based on the chemical structure of the lead compound ETP-46321, a potent PI3K inhibitor, previously reported by our group. The new generated compounds showed good in vitro potency and selectivity, proved to inhibit potently the phosphorylation of AKT in cells and demonstrated to be orally bioavailable, thus becoming potential back-up candidates for ETP-46321.

Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy.

The involvement of the phosphoinositide 3-kinases (PI3Ks) in several diseases, especially in the oncology area, has singled it as one of the most explored therapeutic targets in the last two decades. Many different inhibitor classes have been developed by the industry and academia with a diverse selectivity profile within the PI3K family. In the present manuscript we report a further exploration of our lead PI3K inhibitor ETP-46321 (Martínez González et al.

Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys.

Genetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues.

Paradoxical EU agricultural policies on genetically engineered crops.

European Union (EU) agricultural policy has been developed in the pursuit of laudable goals such as a competitive economy and regulatory harmony across the union. However, what has emerged is a fragmented, contradictory, and unworkable legislative framework that threatens economic disaster. In this review, we present case studies highlighting differences in the regulations applied to foods grown in EU countries and identical imported products, which show that the EU is undermining its own competitiveness in the agricultural sector, damaging both the EU and its humanitarian activities in the developing world.

Rapid identification of ETP-46992, orally bioavailable PI3K inhibitor, selective versus mTOR.

Phosphoinositide-3-kinases (PI3K) are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. PI3K is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the rapid identification of ETP-46992, within 2-aminocarbonyl imidazo [1,2-a] pyrazine series, with suitable pharmacokinetic (PK) properties that allows the establishment of mechanism of action and efficacy in vivo studies.

Biological characterization of ETP-46321 a selective and efficacious inhibitor of phosphoinositide-3-kinases.

Inhibitors of PI3K signaling are of great therapeutic interest in oncology. The phosphoinositide-3-kinase signaling pathway is activated in a variety of solid and non-solid tumors. We have identified an imidazopyrazine derivative, ETP-46321, as a potent inhibitor of PI3Kα [Formula: see text].

Hit to lead evaluation of 1,2,3-triazolo[4,5-b]pyridines as PIM kinase inhibitors.

PIM kinases have become targets of interest due to their association with biochemical mechanisms affecting survival, proliferation and cytokine production. 1,2,3-Triazolo[4,5-b]pyridines were identified as PIM inhibitors applying a scaffold hopping approach. Initial exploration around this scaffold and X-ray crystallographic data are hereby described.

Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.

Nodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, while cancer stem cells and stroma-derived pancreatic stellate cells markedly overexpressed Nodal and Activin, but not TGF-β.