A5042782105- Protein Degradation and Inhibitors
- Retinoids in leukemia and cellular processes
- Histone Deacetylase Inhibitors Research
- Nuclear physics research studies
- Acute Myeloid Leukemia Research
- Click Chemistry and Applications
- Advanced biosensing and bioanalysis techniques
- Multiple Myeloma Research and Treatments
- Nuclear Physics and Applications
- Atomic and Molecular Physics
- Ubiquitin and proteasome pathways
- RNA Interference and Gene Delivery
- Particle accelerators and beam dynamics
- Cancer-related Molecular Pathways
- Muon and positron interactions and applications
- Advanced Fluorescence Microscopy Techniques
- Mass Spectrometry Techniques and Applications
- Advanced Chemical Physics Studies
- Photoreceptor and optogenetics research
- Radioactive Decay and Measurement Techniques
- Particle Accelerators and Free-Electron Lasers
- X-ray Spectroscopy and Fluorescence Analysis
- Chronic Lymphocytic Leukemia Research
- Computational Drug Discovery Methods
- Chronic Myeloid Leukemia Treatments
Dana-Farber Cancer Institute
2010-2018
University of California, San Diego
2008-2013
Imaging Center
2012
Pediatric Oncology Group
2012
Howard Hughes Medical Institute
2012
Harvard University
2010-2011
Brookhaven National Laboratory
1968-1998
Argonne National Laboratory
1947
Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of bromodomain extra-terminal domain (BET) proteins in DLBCL, using integrative chemical genetics functional epigenomics. We observe highly asymmetric loading 4 (BRD4) at enhancers, with approximately 33% all BRD4 localizing to enhancers 1.6% occupied genes. These super-enhancers prove particularly sensitive inhibition, explaining selective effect BET inhibitors...
A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of selective small-molecule inhibitor (JQ1) bromodomain and extraterminal (BET) subfamily epigenetic reader proteins. Here, report potent inhibition testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical crystallographic studies confirm that occupancy BRDT acetyl-lysine binding pocket by...
Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements cytokine receptor subunit receptor–like factor (CRLF2), and other tumors constitutive JAK2 signaling. In this study, we identify G935R, Y931C, E864K mutations within domain that confer resistance across a panel JAK inhibitors, whether present cis V617F (observed MPNs) or R683G B-ALL). do not reduce...
We characterized the enhancer landscape of 66 patients with acute myeloid leukemia (AML), identifying 6 novel subgroups and their associated regulatory loci. These are defined by superenhancer (SE) maps, orthogonal to somatic mutations, distinct leukemic cell states. Examination transcriptional drivers for these epigenomic subtypes uncovers a subset particularly strong SE at retinoic acid receptor alpha (RARA) gene locus. The presence RARA concomitant high levels mRNA predisposes lines ex...
BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo inhibitors prompted need for structurally dissimilar ligands probes function. Using fluorous-tagged multicomponent reactions, we developed focused chemical library around 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis assessment allowed optimization novel based on an...
The decay of 15.8-h ${\mathrm{Ir}}^{186}$ was studied with a double-focusing electron spectrometer, lens and scintillation spectrometers. Several coincidence experiments were also performed. About two-thirds the 101 transitions observed could be fitted into level scheme for ${\mathrm{Os}}^{186}$ consisting ground-state ($K=0$) band, $K=2$ (gamma-vibrational) several other levels. positron spectrum shows at least two branches; branch highest end-point energy...
Transcriptional deregulation is a hallmark of many cancers and exemplified by genomic amplifications the MYC family oncogenes, which occur in at least 20% all solid tumors adults. Targeting transcriptional cofactors cyclin-dependent kinase (CDK9) has emerged as therapeutic strategy to interdict deregulated activity including oncogenic MYC. Here, we report structural optimization small molecule microarray hit, prioritizing maintenance CDK9 selectivity while improving on-target potency overall...
Bromodomains have been pursued intensively over the past several years as emerging targets for development of anticancer and anti-inflammatory agents. It has recently shown that some kinase inhibitors are able to potently inhibit bromodomains BRD4. The clinical activities PLK inhibitor BI-2536 JAK2-FLT3 TG101348 attributed this unexpected polypharmacology, indicating dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, target validation biological...
Spectra of the gamma rays and internal conversion electrons emitted in decay 12-day ${\mathrm{Ir}}^{190}$ have been studied detail. Internal spectra were obtained with aid double-focusing intermediate-image beta spectrometers, a permanent-magnet spectrograph. Gamma-ray by means photoelectric conversion, employing spectrometer, scintillation techniques.These measurements energies relative intensities give coefficients for number transitions. These data, coupled co-incidence studies rays,...
While the decay-scheme of even-even isomer ${\mathrm{Os}}^{190m}(10 min)$ has some similarity with that "rotational" ${\mathrm{Hf}}^{180m}$, it differs from latter in ${\mathrm{Os}}^{190}$ lies transition region between nuclei rotational and those near-harmonic level schemes. It was previously believed lifetime determining ${\mathrm{Os}}^{190m}$ a 620-kev followed by three lower energy gamma rays. We find, however, isomeric is overlooked 38.4-kev $M2$ an...
A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid (AML) and ∼50% myelodysplastic syndromes (MDS). an actionable target for treatment tamibarotene, oral potent selective RARα agonist. Sensitivity to agonist tamibarotene was demonstrated RARA-high but not RARA-low preclinical AML models. The combination plus azacitidine evaluated a phase 2 clinical study 51 newly diagnosed unfit...
The structure of ${\mathrm{Eu}}^{152}$ is great interest, since this nucleus unique in being flanked by two even-even isobars which differ radically from each other shape: ${\mathrm{Sm}}^{152}$ strongly deformed while ${\mathrm{Gd}}^{152}$ spherical. Only states had previously been known ${\mathrm{Eu}}^{152}$: the 13-year ground state (3-) and 9.3-h isomeric (0-). A detailed investigation decay a new 96-min isomer, ${\mathrm{Eu}}^{152{m}_{2}}$, has carried out. This isomer was first reported...
In studying an iridium specimen irradiated for one month in the BNL Reactor and then allowed to cool, a gamma spectrum identical with Ir/sup 192g/ was obtained, but corresponding source strength of 2820 plus or minus 140 disintegrations per sec. As 192/ g is known have 1.45minute isomer, decaying mainly by 58-kev isomeric (E3) transition 74-day ground state, it concluded that observed activity stems from third, longer lived isomer 192/. Afar various studies on lower limit T 1/2 > 5 yr set. (W.D.M.)