1,721,057 research outputs found
Collecting data through high throughput in vitro early toxicity and off-target liability assays to rapidly identify limitations of novel thyromimetics
Full text linkIn order to rapidly identify the phenotypic profile and possible off-target liability effects of novel synthesized thyromimetics for selection of lead compounds for further optimization studies, we performed in vitro screening on a new small library of synthetic thyromimetics. A comprehensive panel of early toxicity assays comprising cytotoxicity on 4 different cell lines (osteosarcoma, U2OS; lung fibroblast, hTERT; human breast adenocarcinoma, MCF7; human embryonic kidney, HEK293), hERG liability, cytochrome P450 inhibition (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoforms), and off-target liability against selected proteins (Aurora B kinase and phosphodiesterase PDE4C1) and epigenetic enzymes (HDAC4, HDAC6, HDAC8, HDAC9 & SIRT7). All the compounds were screened at 10 μM in at least triplicate using well-established in vitro assays with readouts in luminescence or fluorescence polarization mode. The raw data were processed using Microsoft Excel and the Z′ for each assay was calculated (acceptable Z' >0.40). The processed and normalized data were organized in tables and visualized using spider plots. The results which are reported in the present manuscript can be used in prediction studies of early toxicity and off-target liabilities of other thyromimetics using in silico methods. The data reported herein support our research article entitled “Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-Toxicity analysis” by Runfola M., Sestito S., et al. [1
A patent update on PDK1 inhibitors (2015-present)
Full text linkIntroduction: 3-Phosphoinositide-dependent kinase 1 (PDK1), the ‘master kinase of the AGC protein kinase family’, plays a key role in cancer development and progression. Although it has been rather overlooked, in the last decades a growing number of molecules have been developed to effectively modulate the PDK1 enzyme. Areas covered: This review collects different PDK1 inhibitors patented from October 2014 to December 2018. The molecules have been classified on the basis of the chemical structure/type of inhibition, and for each general structure, examples have been discussed in extenso. Expert opinion: The role of PDK1 in cancer development and progression as well as in metastasis formation and in chemoresistance has been confirmed by many studies. Therefore, the pharmaceutical discovery in both public and private institutions is still ongoing despite the plentiful molecules already published. The majority of the new molecules synthetized interact with binding sites different from the ATP binding site (i.e. PIF pocket or DFG-out conformation). However, many researchers are still looking for innovative PDK1 modulation strategy such as combination of well-known inhibitory agents or multitarget ligands, aiming to block, together with PDK1, other different critical players in the wide panorama of proteins involved in tumor pathways
2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS DUAL INHIBITORS OF PDK1/AURA
No full textThe present invention concern a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) in the treatment of pathologies which require a dual inhibitor of PDK1/AurA enzymes such as for instance tumours, particularly glioblastoma
Beyond antioxidant effects: Nature-based templates unveil new strategies for neurodegenerative diseases
Full text linkThe complex network of malfunctioning pathways occurring in the pathogenesis of neurodegenerative diseases (NDDs) represents a huge hurdle in the development of new effective drugs to be used in therapy. In this context, redox reactions act as crucial regulators in the maintenance of neuronal microenvironment homeostasis. Particularly, their imbalance results in the severe compromising of organism’s natural defense systems and subsequently, in the instauration of deleterious OS, that plays a fundamental role in the insurgence and progress of NDDs. Despite the huge efforts in drug discovery programs, the identification process of new therapeutic agents able to counteract the relentless progress of neurodegenerative processes has produced low or no effective therapies. Consequently, a paradigm-shift in the drug discovery approach for these diseases is gradually occurring, paving the way for innovative therapeutical approaches, such as polypharmacology. The aim of this review is to provide an overview of the main pharmacological features of most promising nature-based scaffolds for a possible application in drug discovery, especially for NDDs, highlighting their multifaceted effects against OS and neuronal disorders
2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS DUAL INHIBITORS OF PDK1/AURA
No full textThe present invention concern a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) in the treatment of pathologies which require a dual inhibitor of PDK1/AurA enzymes such as for instance tumours, particularly glioblastoma
Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders
Full text linkThyroid hormones (THs) elicit significant effects on numerous physiological processes, such as growth, development, and metabolism. A lack of thyroid hormones is not compatible with normal health. Most THs effects are mediated by two different thyroid hormone receptor (TR) isoforms, namely TRα and TRβ, with the TRβ isoform known to be responsible for the main beneficial effects of TH on liver. In brain, despite the crucial role of TRα isoform in neuronal development, TRβ has been proposed to play a role in the remyelination processes. Consequently, over the past two decades, much effort has been applied in developing thyroid hormone analogs capable of uncoupling beneficial actions on liver (triglyceride and cholesterol lowering) and central nervous system (CNS) (oligodendrocyte proliferation) from deleterious effects on the heart, muscle and bone. Sobetirome (GC-1) and subsequently Eprotirome (KB2115) were the first examples of TRβ selective thyromimetics, with Sobetirome differing from the structure of thyronines because of the absence of halogens, biaryl ether oxygen, and amino-acidic side chain. Even though both thyromimetics showed encouraging actions against hypercholesterolemia, non-alcoholic steatohepatitis (NASH) and in the stimulation of hepatocytes proliferation, they were stopped after Phase 1 and Phase 2–3 clinical trials, respectively. In recent years, advances in molecular and structural biology have facilitated the design of new selective thyroid hormone mimetics that exhibit TR isoform-selective binding, and/or liver- and tissue-selective uptake, with Resmetirom (MGL-3196) and Hep-Direct prodrug VK2809 (MB07811) probably representing two of the most promising lipid lowering agents, currently under phase 2–3 clinical trials. More recently the application of a comprehensive panel of ADME-Toxicity assays enabled the selection of novel thyromimetic IS25 and its prodrug TG68, as very powerful lipid lowering agents both in vitro and in vivo. In addition to dyslipidemia and other liver pathologies, THs analogs could also be of value for the treatment of neurodegenerative diseases, such as multiple sclerosis (MS). Sob-AM2, a CNS- selective prodrug of Sobetirome has been shown to promote significant myelin repair in the brain and spinal cord of mouse demyelinating models and it is rapidly moving into clinical trials in humans. Taken together all these findings support the great potential of selective thyromimetics in targeting a large variety of human pathologies characterized by altered metabolism and/or cellular differentiation
COMPOSTI 2-OXO-1,2-DIIDROPIRIDIN-3-CARBOSSAMMIDE E LORO USO COME INIBITORI DI PDK1
No full textThe invention concerns 2-oxo-1,2-dihydropyridine-3-carboxamide compounds
10 and their use as inhibitors and/or modulators of PDK1
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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