The two tandem bromodomains of the BET proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1 whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET targeted therapies.

The CEBAF large acceptance spectrometer (CLAS) is used to study photo- and electro-induced nuclear and hadronic reactions by providing efficient detection of neutral and charged particles over a good fraction of the full solid angle. A collaboration of about 30 institutions has designed, assembled, and commissioned CLAS in Hall B at the Thomas Jefferson National Accelerator Facility. The CLAS detector is based on a novel six-coil toroidal magnet which provides a largely azimuthal field distribution. Trajectory reconstruction using drift chambers results in a momentum resolution of 0.5% at forward angles. Cherenkov counters, time-of-flight scintillators, and electromagnetic calorimeters provide good particle identification. Fast triggering and high data-acquisition rates allow operation at a luminosity of View the MathML source. These capabilities are being used in a broad experimental program to study the structure and interactions of mesons, nucleons, and nuclei using polarized and unpolarized electron and photon beams and targets. This paper is a comprehensive and general description of the design, construction and performance of CLAS

Measurement of two-and three-nucleon shortrange correlation probabilities in nuclei KS The ratios of inclusive electron scattering cross sections of 4 He, 12 C, and 56 Fe to 3 He have been measured at 1 < x B < 3. At Q 2 > 1:4 GeV 2 , the ratios exhibit two separate plateaus, at 1:5 < x B < 2 and at x B > 2:25. This pattern is predicted by models that include 2-and 3-nucleon short-range correlations (SRC). Relative to A 3, the per-nucleon probabilities of 3-nucleon SRC are 2.3, 3.1, and 4.4 times larger for A 4, 12, and 56. This is the first measurement of 3-nucleon SRC probabilities in nuclei.

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9 þ acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers. Cancer Res; 75(23); 5106-19. Ó2015 AACR.

Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.