1,2,3-Triazole-totarol conjugates as potent PIP5K1α lipid kinase inhibitors.

The human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a key role in the development of prostate cancer. In this work, seventeen derivatives of the natural diterpene totarol were prepared by copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of the correspondingO-propargylated totarol with aryl or alkyl azides and screened for their inhibitory activities toward hPIP5K1α. Five compounds, 3a, 3e, 3f, 3i, and 3r, strongly inhibited the enzyme activity with IC values of 1.

Impact of surgical complications on hospital costs and revenues: retrospective database study of Medicare claims.

To compare the length of stay, hospital costs and hospital revenues for Medicare patients with and without a subset of potentially preventable postoperative complications after major noncardiac surgery. Retrospective data analysis using the Medicare Standard Analytical Files, Limited Data Set, 5% inpatient claims files for years 2016-2020. In 74,103 claims selected for analysis, 71,467 claims had no complications and 2636 had one or more complications of interest.

Natural Compounds Isolated from Are Potent Inhibitors of Human Protein Kinase CK2.

A large number of secondary metabolites have been isolated from the filamentous fungus and have been described before. Fourteen of these natural compounds were evaluated in vitro in the present study for their inhibitory activity towards the cancer target CK2. Among these compounds, stachybotrychromene C, stachybotrydial acetate and acetoxystachybotrydial acetate turned out to be potent inhibitors with IC values of 0.

Autodisplay of human PIP5K1α lipid kinase on Escherichia coli and inhibitor testing.

The human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a major role in the PI3K/AKT/mTOR signaling pathway. As it has been shown before that hPIP5K1α is involved in the development of different types of cancer in particular prostate cancer, inhibitors of the enzyme might be a new option for the treatment of this disease. Here we report on the expression of hPIP5K1α on the surface of E.

In Silico and In Vitro Studies of Natural Compounds as Human CK2 Inhibitors.

Background: Casein Kinase 2 (CK2) is a ubiquitous cellular serine-threonine kinase with broad spectrum of substrates. This enzyme is widely expressed in eukaryotic cells and is overexpressed in different human cancers. Thus, the inhibition of CK2 can induce the physiological process of apoptosis leading to tumor cell death.

QSAR Model of Indeno[1,2-]indole Derivatives and Identification of -isopentyl-2-methyl-4,9-dioxo-4,9-Dihydronaphtho[2,3-]furan-3-carboxamide as a Potent CK2 Inhibitor.

Casein kinase II (CK2) is an intensively studied enzyme, involved in different diseases, cancer in particular. Different scaffolds were used to develop inhibitors of this enzyme. Here, we report on the synthesis and biological evaluation of twenty phenolic, ketonic, and -quinonic indeno[1,2-]indole derivatives as CK2 inhibitors.

Design, synthesis and biological evaluation of new embelin derivatives as CK2 inhibitors.

A new series of furan embelin derivatives was synthesized and characterized as ATP-competitive CK2 inhibitors. The new compounds were efficiently synthesized using a multicomponent approach from embelin (1), aldehydes and isonitriles through a Knoevenagel condensation/Michael addition/heterocyclization. Several compounds with inhibitory activities in the low micromolar or even submicromolar were identified.

Development of an in vitro screening assay for PIP5K1α lipid kinase and identification of potent inhibitors.

The human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) participates in the phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Despite the evidence that hPIP5K1α plays a role in the development of prostate cancer (PCa), only one inhibitor is known to date. With the aim of identifying new inhibitors, a nonradiometric assay for measurement of the hPIP5K1α enzyme activity was developed.

In Vitro and in Silico Evaluation of Bikaverin as a Potent Inhibitor of Human Protein Kinase CK2.

Protein kinase CK2 is an emerging target for therapeutic intervention in human diseases, particularly in cancer. Inhibitors of this enzyme are currently in clinical trials, indicating the druggability of human CK2. By virtual screening of the ZINC database, we found that the natural compound bikaverin can fit well in the ATP binding site of the target enzyme CK2.

Human α-casein induces IL-8 secretion by binding to the ecto-domain of the TLR4/MD2 receptor complex.

Background: The milk protein α-casein was recently reported to induce secretion of proinflammatory cytokines via Toll-like receptor 4 (TLR4). In this study, α-casein was identified as binder of theTLR4 ecto domain.

Methods: IL-8 secretion after stimulation of TLR4/MD2 (myeloid differentiation factor 2)/CD14 (cluster of differentiation 14)-transfected HEK293 cells (TLR4) and Mono Mac 6 cells (MM6) with recombinant α-casein, or LPS as control was monitored.

Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining.

Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones.

Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate.

Assays that can determine the response of tumor cells to cancer therapeutics could greatly aid the selection of drug regimens for individual patients. However, the utility of current functional assays is limited, and predictive genetic biomarkers are available for only a small fraction of cancer therapies. We found that the single-cell mass accumulation rate (MAR), profiled over many hours with a suspended microchannel resonator, accurately defined the drug sensitivity or resistance of glioblastoma and B-cell acute lymphocytic leukemia cells.

1st Joint European Conference on Therapeutic Targets and Medicinal Chemistry (TTMC 2015).

The European Conference on Therapeutic Targets and Medicinal Chemistry is a new two-day meeting on drug discovery that is focused on therapeutic targets and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, NMR studies, fragment screening, in vitro assays, in vivo assays, structure activity relationships, autodisplay. Abstracts of keynote lectures, plenary lectures, junior lectures, flash presentations, and posters presented during the meeting are collected in this report.

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas.

Purpose: p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM.

Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo.

Aiming at the development of new drugs for the treatment of prostate cancer, the effects of steroidal compounds and one non-steroidal substance on androgen biosynthesis were evaluated in vitro and in vivo. Sa 40 [17-(5-pyrimidyl)androsta-5,16-diene-3beta-ol], its 3-acetyl derivate Sa 41 and BW 19 [3,4-dihydro-2-(4-imidazolylmethyl)-6-methoxy-1-methyl-naphthalene] are compounds from our group, which have been developed as inhibitors of CYP 17 (17alpha-hydroxylase-C17, 20-lyase, the key enzyme in androgen biosynthesis). They have been compared with CB 7598 [abiraterone: 17-(3-pyridyl)androsta-5,16-diene-3beta-ol], its 3-acetyl compound CB 7630 and ketoconazole, compounds which already have been used clinically.

C16 and C17 substituted derivatives of pregnenolone and progesterone as inhibitors of 17alpha-hydroxylase-C17, 20-lyase: synthesis and biological evaluation.

17 alpha-hydroxylase-C17, 20-lyase (P450 17, CYP 17) is a key enzyme in androgen biosynthesis and a target for the treatment of prostate cancer. In order to find novel inhibitors for this enzyme, several compounds bearing different moieties able to complex with the heme iron located in the active site of the enzyme were synthesized. The moieties were introduced into the 16-position of pregnenolone and progesterone.

Inhibition of CYP 17, a new strategy for the treatment of prostate cancer.

Androgens are growth factors for approximately 80 percent of all prostate cancers. Suppressing androgen biosynthesis is therefore an important therapeutic strategy in order to inhibit tumor growth. Unfortunately, the drugs currently applied to lower androgen levels only affect testicular androgen production.