The most frequently mutated oncogene in cancer is KRAS, which utilizes alternative fourth exons to generate two gene products, KRAS4A and KRAS4B, that differ only in their C-terminal membrane-targeting region 1. Because oncogenic mutations occur in exons 2 or 3, when KRAS is activated by mutation two constitutively active KRAS proteins are encoded, each capable of transforming cells 2. No functional distinctions among the splice variants have been established. Oncogenic KRAS alters tumor metabolism 3. Among these alterations is increased glucose uptake and glycolysis, even in the presence of abundant oxygen 4 (the Warburg Effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes 3-5 , direct regulation of metabolic enzymes has not been examined. We report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, establishing HK1 as an effector of KRAS4A. The interaction is unique to KRAS4A because the palmitoylation/depalmitoylation cycle of this RAS isoform permits co-localization with HK1 on the outer mitochondrial membrane (OMM). KRAS4A expression in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.

TASK-1 is a two-pore domain potassium channel that is important to modulating cell excitability, most notably in the context of neuronal pathways. In order to leverage TASK-1 for therapeutic benefit, its physiological role needs better characterization; however, designing selective inhibitors that avoid the closely related TASK-3 channel has been challenging. In this study, a series of bis-amide derived compounds were found to demonstrate improved TASK-1 selectivity over TASK-3 compared to reported inhibitors. Optimization of a marginally selective hit led to analog 35 which displays a TASK-1 IC50 = 16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.

Mutant KRAS drives oncogenesis when associated with the plasma membrane. Fehrenbacher et al. identify GPR31, a G protein–coupled receptor, as a secretory pathway chaperone that guides the KRAS protein to the plasma membrane.

Pimeloyl-acyl carrier protein (ACP) methyl esterase is an α/β-hydrolase that catalyzes the last biosynthetic step of pimeloyl-ACP, a key intermediate in biotin biosynthesis. Intriguingly, multiple nonhomologous isofunctional forms of this enzyme that lack significant sequence identity are present in diverse bacteria. One such esterase, Escherichia coli BioH, has been shown to be a typical α/β-hydrolase fold enzyme. To gain further insights into the role of this step in biotin biosynthesis, we have determined the crystal structure of another widely distributed pimeloyl-ACP methyl esterase, Haemophilus influenzae BioG, at 1.26 Å. The BioG structure is similar to the BioH structure and is composed of an α-helical lid domain and a core domain that contains a central seven-stranded β-pleated sheet. However, four of the six α-helices that flank both sides of the BioH core β-sheet are replaced with long loops in BioG, thus forming an unusual α/β-hydrolase fold. This structural variation results in a significantly decreased thermal stability of the enzyme. Nevertheless, the lid domain and the residues at the lid-core interface are well conserved between BioH and BioG, in which an analogous hydrophobic pocket for pimelate binding as well as similar ionic interactions with the ACP moiety are retained. Biochemical characterization of site-directed mutants of the residues hypothesized to interact with the ACP moiety supports a similar substrate interaction mode for the two enzymes. Consequently, these enzymes package the identical catalytic function under a considerably different protein surface.

Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).

Eurotium cristatum is the dominant fungi species in Fuzhuan brick tea (FBT), which may be responsible for the color, taste, and associated health benefits. In this study, eight E. cristatum strains were first isolated from various brands of FBT in China. Six benzaldehyde derivatives 1–6 were then isolated and characterized from these FBT-derived E. cristatum, four of which were also present in the spores of E. cristatum. The anti-inflammatory activities of these benzaldehyde derivatives were evaluated in lipopolysaccharide-induced RAW264.7 cells. These compounds could inhibit the expression both of inducible nitroxide synthase and cyclooxygenase-2. Our results suggest that the benzaldehyde derivatives from E. cristatum may be at least partially responsible for the observed health benefits of FBT.

Background The global prevalence of traditional Chinese medicine stimulates the prosperous development of herb medicines, but the annual generation of massive herb residues becomes big issues about environmental pollution and waste of resources. Microbes play important roles in the circulation of substances in nature, and endophytes represent an underexplored microbial resource possessing the unique symbiotic relationship with plants, not only for discovery of secondary metabolites, but also for potential green recycling of herb residues. Results The recycling capacities of several endophytic strains were respectively evaluated via solid state fermentation with herb residues of commercial Huazhenghuisheng oral-liquid (HOL). Among them, Aspergillus cristatus CB10002, a probiotic fungus isolated from Chinese Fu-brick tea, was competent to recycle HOL residues for the production of medicinal valuable anthraquinones, in which four of them, especially citreorosein with significant anti-obesity activity, were first discovered in A. cristatus . Subsequent quantitative analysis showed that about 2.0 mg/g citreorosein and 7.5 mg/g total anthraquinones could be obtained after 35-day fermentation, which was very competitive and economically beneficial. Further nutritional comparisons also revealed that the recycling process indeed ameliorated the nutrients of HOL residues, and thus proposed a possibility to directly dispose the final leftovers as a compost organic fertilizer. Conclusions The endophytic and probiotic fungus A. cristatus CB10002 isolated from Chinese Fu-brick tea was screened out to effectively reutilize HOL residues for the production of nine medicinal valuable anthraquinones, whose biosynthesis may be regulated by the induction of HOL residues. The competitive yields of these anthraquinones, as well as the certain composting properties of final leftovers, have made the microbial recycling of HOL residues economically beneficial. Our work demonstrated a promising applied potential of A. cristatus in reutilization of herb residues, and provided a practical strategy for sustainable and value-added microbial recycling of herb residues. Electronic supplementary material The online version of this article (10.1186/s12934-019-1150-9) contains supplementary material, which is available to authorized users.