Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study.

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia.

RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival.

Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

Background: Indisulam possesses anticancer properties through down-regulation of various cell-cycle checkpoint molecules, thereby blocking the phosphorylation of retinoblastoma protein and inducing p53 and p21. Indisulam exhibits synergy with nucleoside analogs and topoisomerase inhibitors.

Methods: The authors designed a phase 2 study of indisulam in combination with idarubicin and cytarabine in patients who had relapsed/refractory acute myeloid leukemia AML and high-risk myelodysplastic syndrome.

Selective degradation of splicing factor CAPERα by anticancer sulfonamides.

Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4 mediated ubiquitination in human cancer cell lines.

Oscillatory potentials in electroretinogram as an early marker of visual abnormalities in vitamin A deficiency.

Vitamin A deficiency (VAD) caused by malnutrition and certain intestinal diseases induces visual impairments, including night blindness and photoreceptor cell dysfunction as indicated by reduced a‑ and b‑waves in an electroretinogram (ERG). The effects of VAD on the inner retinal layer cells, including amacrine and ganglion cells, remain to be elucidated. The functions of these cells are reflected in oscillatory potentials (OPs), another component of the ERG.

Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models.

Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models.

Highly accurate chemical formula prediction tool utilizing high-resolution mass spectra, MS/MS fragmentation, heuristic rules, and isotope pattern matching.

Mass spectrometry is commonly applied to qualitatively and quantitatively profile small molecules, such as peptides, metabolites, or lipids. Modern mass spectrometers provide accurate measurements of mass-to-charge ratios of ions, with errors as low as 1 ppm. Even such high mass accuracy, however, is not sufficient to determine the unique chemical formula of each ion, and additional algorithms are necessary.

Practical metabolomics in drug discovery.

Importance Of The Field: Metabolomics is increasingly becoming an important field in the pharmaceutical industry to support the discovery and development of therapeutic agents. It allows the comprehensive and simultaneous profiling of hundreds of discrete biologically important molecules, including amino acids, sugars, lipids and exogenous substances from biological fluids and tissues. Metabolomics is the 'omics' field that most represents the interplay of internal biological regulation and external environmental influences on disease, thereby being of particular importance to disease mitigation and management.

Polar anionic metabolome analysis by nano-LC/MS with a metal chelating agent.

We have developed a practical method for the comprehensive analysis of polar anionic metabolites in biological samples with the use of a nano-LC/MS system. A polyamine-bonded polymer-based apHera NH2 column, which is compatible with ammonium carbonate buffer, effectively retained anionic polar metabolites, such as organic acids, sulfates, and phosphates, but multiply phosphorylated or carboxylated compounds showed highly distorted peak shapes on chromatograms. We found that addition of a trace amount of the metal chelating reagent ethylenediaminetetraacetic acid (EDTA) to the sample solution dramatically improved peak shapes of multiply charged anionic compounds, even though the mass spectra showed no trace of adduct ions in the absence of EDTA.

Quantitative phosphorus metabolomics using nanoflow liquid chromatography-tandem mass spectrometry and culture-derived comprehensive global internal standards.

Highly sensitive and quantitative analytical methods are essential for metabolomics. In this report, we introduce an analytical method focused on endogenous phosphorus metabolites, using nanoflow liquid chromatography-electrospray ionization tandem mass spectrometry (nanoLC-ESI-MS/MS) and culture-derived isotope-tagged metabolites as global internal standards for quantitative metabolomics. The nanoLC-ESI-MS/MS method employing a stone-arch microcolumn with amino propyl silica gel achieved good separation of phosphorus metabolites with forty- to hundred-fold increase of sensitivity compared with semimicro flow LC-ESI-MS.

Stereochemistry of pladienolide B.

Pladienolide B is a 12-membered macrolide isolated from Streptomyces platensis Mer-11107. It showed potent in vitro and in vivo antitumor activities and is a potential lead for novel antitumor agents. The absolute configurations at ten chiral centers were determined on the basis of spectral data of pladienolide B and its chemical transformation products.

Schulzeines A-C, new alpha-glucosidase inhibitors from the marine sponge Penares schulzei.

Three new alpha-glucosidase inhibitors, schulzeines A-C (1-3), were isolated from the marine sponge Penares schulzei. Their structures were elucidated by spectral analysis and chemical degradations to be the isoquinoline alkaloids, encompassing two amino acids, and C(28) fatty acid, the last of which was sulfated. Absolute stereochemistry of schulzeines was determined by application of the modified Mosher analysis to fragments obtained by chemical degradation.

Callyspongynic acid, a polyacetylenic acid which inhibits alpha-glucosidase, from the marine sponge Callyspongia truncata.

A new polyacetylenic acid, callyspongynic acid (1), was isolated as an alpha-glucosidase inhibitor from the marine sponge Callyspongia truncata. Its structure was determined by spectroscopic and chemical methods.