Somatic point mutations
at a key arginine residue (R132) within
the active site of the metabolic enzyme isocitrate dehydrogenase 1
(IDH1) confer a novel gain of function in cancer cells, resulting
in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite.
Elevated 2-HG levels are implicated in epigenetic alterations and
impaired cellular differentiation. IDH1 mutations have been described
in an array of hematologic malignancies and solid tumors. Here, we
report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1
mutant enzyme that exhibits profound 2-HG lowering in tumor models
and the ability to effect differentiation of primary patient AML samples
ex vivo. Preliminary data from phase 1 clinical trials enrolling patients
with cancers harboring an IDH1 mutation indicate that AG-120 has an
acceptable safety profile and clinical activity.
Using both surveys and the experience sampling method (ESM), community violence exposure, social support factors, and depressive and anxiety symptoms were assessed longitudinally among inner-city African American adolescents. Moderator models were tested to determine protective factors for youth exposed to community violence. Several social support factors emerged as protective-stabilizing forces for witnesses of violence both cross-sectionally and longitudinally, including maternal closeness, time spent with family, social support, and daily support (ESM). Contrary to hypotheses, several social support factors demonstrated a promotive-reactive effect such that, in conditions of high victimization, they failed to protect youth from developing symptoms. Effects did not differ by outcome or sex, though sex differences in findings emerged. Protective-stabilizing effects occurred more for witnessing violence, whereas promotive-reactive patterns occurred more for victimization. Results affirm social support factors as protective from the adverse effects of violence exposure, but they also suggest that some factors typically conceived as contributing to resilience might at times fail to protect youth in conditions of extreme risk.
The solution-phase synthesis of organic compounds as mixtures rather than in individual pure form offers efficiency advantages that are negated by the difficulty in separating and identifying the components of the final mixture. Here, a strategy for mixture synthesis that addresses these separation and identification problems is presented. A series of organic substrates was tagged with a series of fluorous tags of increasing fluorine content. The compounds were then mixed, and multistep reactions were conducted to make enantiomers or analogs of the natural product mappicine. The resulting tagged products were then demixed by fluorous chromatography (eluting in order of increasing fluorine content) to provide the individual pure components of the mixture, which were detagged to release the final products.
Inhibitors of mutant
isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated
enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate
(2-HG) and are under clinical investigation for the treatment of several
cancers harboring an IDH mutation. Herein, we describe the discovery
of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor
of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to
characterize the compound binding site, leading to an understanding
of the dual mutant inhibition. Furthermore, vorasidenib penetrates
the brain of several preclinical species and inhibits 2-HG production
in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib
represents a novel dual mIDH1/2 inhibitor and is currently in clinical
development for the treatment of low-grade mIDH glioma.
Fluorous synthesis involves tagging an organic substrate with a fluorinated tag for the purposes of
separation. To date, techniques of fluorous synthesis have relied on liquid−liquid extractions. This paper applies
a simple solid−liquid extraction procedure over fluorous reverse-phase silica gel (silica with a fluorocarbon
bonded phase) for use in fluorous synthesis. Four amino acids were tagged on nitrogen with the C9F19CO−
group, and the resulting acids were coupled in a parallel experiment with an excess of four amines. The resulting
16 crude fluorous amide products were separated from all the coupling reagents and excess amine by two-stage filtration through fluorous silica. In 15 of the 16 cases, the products were isolated in good to excellent
yield and purity. All of the products are soluble in organic solvents and none is expected to have any significant
solubility in fluorous solvents, so the experiment dramatically illustrates the advantages of the solid−liquid
extraction over the liquid−liquid extraction. Future prospects for application of fluorous silica are briefly
discussed.
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