Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1R132H mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG–mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.

A thiolated bis(cobalt) cofacial diporphyrin chemisorbed on an edge plane pyrolytic graphite electrode has the electrocatalytic activity of a four-electron (n g 3.6) dioxygen reduction catalyst. When chemisorbed on a gold electrode surface, the same catalyst exhibits the activity of only a two-electron catalyst, producing hydrogen peroxide (n ) 2.1). The edge plane graphite surface thus plays a crucial, but not understood, role in designed dioxygen reduction catalysis. Analysis of X-ray photoelectron spectroscopy and UV-vis results is consistent with the rings of the thiolated porphyrins being coplanar to the Au electrode plane. A structurally modified catalyst exhibits greater coplanarity and a slight increase in activity (n ≈ 2.4). The present results set the stage for a strategy of cochemisorbing functionalities onto the thiolated diporphyrin-coated Au surface, seeking those functionalities which will chemically mimic the graphite surface and elevate the catalytic reactivity to a four-electron dioxygen reduction. Such functionalities could include host-guest cochemisorption of putative carbon surface ligands within the porphyrin electrode cavity. † Present address: Collman, J. P.; Hutchison, J. E.; Lopez, M. A.; Tabard, A.; Guilard, R.; Seok, W. K.; Ibers, J. A.; L'Her, M. J. Am. Chem. Soc. 1992, 114, 9869-9877.(3) (a) Collman, J. P.; Hendricks, N. H.; Leidner, C. R.; Ngameni, E.; L'Her, M. Inorg. Chem. 1988, 27, 387. (b) Collman, J. P.; Wagenknecht, P. S.; Hutchison, J. E.

A number of iridium porphyrins adsorbed on pyrolytic edge plane graphite electrodes have been examined for their electrocatalytic activity toward the four-electron reduction of dioxygen. Their behavior provides insight into the mechanisms by which the iridium porphyrins accomplish this electrocatalysis. Certain iridium porphyrins are found to reduce dioxygen to water via a four-electron pathway in a monometallic fashion. Axial ligation from the edge plane graphite electrode to the iridium metal center is believed to be essential for the catalytic reduction of dioxygen to occur. We propose the active species to be an Ir(II) center. The electrocatalytic behavior of all of the iridium porphyrins which have been examined can be explained by the transformation of these

Platelets are important mediators of blood coagulation that lack nuclei, but contain mitochondria. Although the presence of mitochondria in platelets has long been recognized, platelet mitochondrial function remains largely unaddressed. On the basis of a small amount of literature that suggests platelet mitochondria are functional, we hypothesized that the inhibition of platelet mitochondria disrupts platelet function and platelet-activated blood coagulation. To test this hypothesis, members of the tetrazole, thiazole, and 1,2,3-triazole families of small molecule heterocycles were screened for the ability to inhibit isolated mitochondrial respiration and coagulation of whole blood. The families of heterocycles screened were chosen on the basis of the ability of the heterocycle family to inhibit a biomimetic model of cytochrome c oxidase (CcO). The strength of mitochondrial inhibition correlates with each compound's ability to deter platelet stimulation and platelet-activated blood clotting. These results suggest that for this class of molecules, inhibition of blood coagulation may be occurring through a mechanism involving mitochondrial inhibition. Platelets are directly involved in a number of functions necessary for clotting, including recognition of vascular lesions, triggering activation of the coagulation cascade, and activation of other platelets. The platelet membrane serves as a scaffold for clot formation, and platelets are involved in the activation and cocatalysis of reactions involving many of the soluble clotting factors (1). Like red blood cells, platelets lack nuclei and consequently are unable to replace damaged proteins encoded in the nuclear genome. However, unlike red blood cells, platelets contain actively metabolizing mitochondria (2). Some hints as to the role these mitochondria play in platelet function have been elucidated (3). Along with glycogen granules, platelet mitochondria provide energy that is needed at least indirectly for platelet aggregation and secretion of procoagulant molecules (4). More direct evidence of a role for mitochondria in coagulation rests on observations that changes in the permeability of mitochondrial membranes are linked to changes in coagulation activity (5, 6). These facts imply that inhibition of platelet mitochondrial function should have an inhibitory effect upon platelet-activated blood coagulation.Experimental investigation led to the discovery of three families of small molecule heterocycles that reversibly inhibit mitochondrial respiration and attenuate platelet-activated blood coagulation. These three families of compounds comprise unique examples of a class of anticoagulants proposed to inhibit blood clotting through a mitochondrial mechanism (Fig. 1).The discovery of these particular families of platelet inhibitory molecules occurred after initial work from the Collman laboratory related to biomimetic modeling of cytochrome c oxidase (CcO). CcO is the terminal enzyme in the electron transport chain that catalyzes the four-electron reduction of O 2...

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