Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.

Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.

ABSTRACT:MDR1/ABCB1, MRP2/ABCC2, and breast cancer resistance protein (BCRP)/ABCG2 are expressed in the liver and intestine and contribute to the disposition of many drugs. Rosuvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor for the treatment of patients with dyslipidemia, is primarily excreted via bile as unchanged drug. The present study was designed to determine whether rosuvastatin is transported by MDR1, MRP2, and BCRP. The apparent permeability value for rosuvastatin across MDR1-Madin-Darby canine kidney cells was low (ϳ8 nm/s), and no directional transport was observed. Rosuvastatin uptake into control Sf9 membranes and membranes expressing MRP2 was similar in the presence or absence of GSH. In contrast, ATP dramatically stimulated rosuvastatin uptake into membranes expressing BCRP, but not control membranes. Rosuvastatin transport occurred into an osmotically sensitive space and was saturable. An EadieHofstee analysis suggested that there were two transport sites in BCRP, with an apparent K m of 10.8 M for the high affinity site and 307 M for the low affinity site. These data demonstrate that rosuvastatin is transported efficiently by BCRP and suggest that BCRP plays a significant role in the disposition of rosuvastatin.

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These results demonstrate the existence of a cross-talk between the nitrate-nitrite-NO pathway and the NOS-dependent pathway in control of vascular NO homeostasis.