Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2 R140Q -mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies. SIGNIFICANCE:Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478-93.

Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to D-2-hydroxyglutarate (D-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or D-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.isocitrate dehydrogenase | cartilage tumor | hedgehog E nchondromas, one of the most common benign tumors occurring in bone, are present in more than 3% of the population (1, 2). They are composed of cells derived from chondrocytes and occur as solitary lesions or multiple lesions in enchondromatosis syndromes (Ollier disease or Maffucci syndrome-in the latter, enchondromas are associated with vascular malformations). Clinical problems caused by enchondromas include pain, fractures, and skeletal deformity. There is a potential for malignant progression to chondrosarcoma that may be greater than 50% in some cases of multiple enchondromatosis (i.e., Maffucci syndrome) (3-7). Many chondrosarcomas are thought to derive from enchondromas, and such sarcomas are termed central chondrosarcomas (3).The hedgehog (Hh) signaling pathway is constitutively active in enchondromas and chondrosarcomas (8,9). Hh is important in growth-plate chondrocyte differentiation, where it cooperates with parathyroid hormone-like hormone in a negative feedback loop to inhibit the differentiation of proliferative growth-plate chondrocytes (6,(10)(11)(12)(13)(14). Disruption of this feedback loop can result in either skeletal dysplasias with abnormal bone growth or enchondromas; 5% of enchondromas harbor mutation in parathyroid hormone-like hormone receptor (PTHR1), resulting in activation of Hh signaling (6,(10)(11)(12)(13)(14), and expression of a mutant PTHR1 or overexpression of the Hh-regulated transcription factor Gli2 under the Col2a1 promoter causes enchondroma-like cartilage lesions to develop adjacent to the growth-plate ...

Water serves as an inert environment for the dispersion and application of many kinds of herbicides. Viologen compounds, a type of widely used but highly toxic herbicide, are stable in bulk water, whose half-life can be up to 23 weeks in natural water, imposing a severe health risk to mammals. In this study, we present the striking results of the spontaneous and ultrafast reduction-induced degradation of three viologen compounds in water microdroplets and provide the concentration, time, temperature dependence, mechanism, and scale-up of the reactions. We postulate that the electrons existing at the air−water interface of the microdroplets due to the unique redox potential therein initiate the reduction, from which further degradation occurs. The host−guest complexation between cucurbit[7]uril and viologens only slightly changes the redox potential of viologens in the bulk but completely inhibits the reactions in microdroplets, adding to the uniqueness of the redox potentials at the air−water interfaces of microdroplets. Taken together, microdroplets might have been functioning as naturally occurring ubiquitous tiny electrochemical cells for a plethora of unique redox reactions that were thought to be impossible in the bulk water.

In spite of the absence of a macroscopic magnetic moment, an antiferromagnet is spin-polarized on an atomic scale. The electric current passing through a conducting antiferromagnet is polarized as well, leading to spin-transfer torques when the order parameter is textured, such as in antiferromagnetic noncollinear spin valves and domain walls. We report a first principles study on the electronic transport properties of antiferromagnetic systems. The current-induced spin torques acting on the magnetic moments are comparable with those in conventional ferromagnetic materials, leading to measurable angular resistances and current-induced magnetization dynamics. In contrast to ferromagnets, spin torques in antiferromagnets are very nonlocal. The torques acting far away from the center of an antiferromagnetic domain wall should facilitate current-induced domain wall motion.

Key Points AG-348 is a small-molecule allosteric activator of WT red cell pyruvate kinase as well as mutant enzymes associated with hemolytic anemia. Activity in vitro, in mice, and in red blood cells suggests it may address the underlying molecular pathology in PK deficiency patients.

The C-terminal domain of the bacterial transcription antiterminator RfaH undergoes a dramatic all-α-helix to all-β-barrel transition when released from its N-terminal domain. These two distinct folding patterns correspond to different functions: the all-α state acts as an essential regulator of transcription to ensure RNA polymerase binding, whereas the all-β state operates as an activator of translation by interacting with the ribosomal protein S10 and recruits ribosomal mRNA. Accordingly, this drastic conformational change enables RfaH to physically couple the transcription and translation processes in gene expression. To understand the mechanism behind this extraordinary functionally relevant structural transition, we constructed Markov state models using an adaptive seeding method. The constructed models highlight several parallel folding pathways with heterogeneous molecular mechanisms, which reveal the folding kinetics and atomic details of the conformational transition.

Oxidative C–H/N–H cross-coupling has emerged as an atom-economical method for the construction of C–N bonds. Conventional oxidative C–H/N–H coupling requires at least one of the following: high temperatures, strong oxidizers, transition metal catalysts, organic solvents, light, and electrochemical cells. In this study, by merely spraying the water solutions of the substrates into microdroplets at room temperature, we show a series of oxidative C–H/N–H coupling products that are strikingly produced in a spontaneous and ultrafast manner. The reactions are accelerated by six orders of magnitude compared to the same reactions in the bulk. It has been previously proposed by fluorescence microscopy and theory that the spontaneously generated electric field at the microdroplets peripheries can be in the ∼109 V/m range. Based on mass spectrometric analysis of key radical intermediates, we opine that the ultrahigh electric field catalytically oxidizes the substrates by removing an electron, which further promotes C/N coupling. Taken together, we anticipate that microdroplet chemistry will be an avenue rich in green opportunities of constructing C-heteroatom bonds.

Despite the high stability of bulk water, water microdroplets possess strikingly different properties, such as the presence of hydroxyl radicals (OH⋅) at the air–water interface. Previous studies exhibited the recombination of OH⋅ into H2O2 molecules and the capture of OH⋅ by oxidizing other molecules. By spraying pure water microdroplets into a mass spectrometer, we detected OH⋅ in the form of (H4O2)+ that is essentially OH⋅−H3O+, a hydroxyl radical combined with a hydronium cation through hydrogen bonding. We also successfully captured it with two OH⋅ scavengers, caffeine and melatonin, and key oxidation radical intermediates that bear important mechanistic information were seen. It is suggested that some previous reactions involving (H4O2)+ should be attributed to reactions with OH⋅−H3O+ rather than with the water dimer cation (H2O−OH2)+.