A5003797094- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Cancer Immunotherapy and Biomarkers
- CAR-T cell therapy research
- Ubiquitin and proteasome pathways
- Immune Cell Function and Interaction
- Traditional and Medicinal Uses of Annonaceae
- Histone Deacetylase Inhibitors Research
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Synthesis and Biological Activity
- Cannabis and Cannabinoid Research
- Peptidase Inhibition and Analysis
- Carbohydrate Chemistry and Synthesis
- Pancreatic function and diabetes
- Genomics and Chromatin Dynamics
- Single-cell and spatial transcriptomics
- vaccines and immunoinformatics approaches
- interferon and immune responses
- Advanced biosensing and bioanalysis techniques
- Alcohol Consumption and Health Effects
- Diet, Metabolism, and Disease
- GABA and Rice Research
- Plant Virus Research Studies
- Diabetes Treatment and Management
Unity Biotechnology (United States)
2017-2018
Merck & Co., Inc., Rahway, NJ, USA (United States)
2008-2018
Scripps Research Institute
2006-2008
Target (United States)
2008
Johnson & Johnson (United States)
2007
University of Kansas
2002-2004
University of Michigan–Ann Arbor
2004
Emory University
2002
Acetylation of histone H3 at lysine 27 is a well-defined marker enhancer activity. However, the functional impact this modification enhancers poorly understood. Here, we use chemical genetics approach to acutely block function cAMP response element binding protein (CREB) (CBP)/P300 bromodomain in models hematological malignancies and describe consequent loss H3K27Ac specifically from enhancers, despite continued presence CBP/P300 chromatin. Using dissect role identify critical for production...
Bromodomains, small protein modules that recognize acetylated lysine on histones, play a significant role in the epigenome, where they function as "readers" ultimately determine functional outcome of post-translational modification. Because initial discovery selective BET inhibitors have helped define family oncology and inflammation, bromodomains continued to garner most attention any other bromodomain. More recently, non-BET bromodomain are potent been disclosed for ATAD2, CBP, BRD7/9,...
Resistance invariably develops to antiandrogen therapies used treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required maintain growth of cancer. To exploit this vulnerability, developed a novel small-molecule inhibitor bromodomain blocks cancer in vitro and vivo Molecular dissection consequences drug treatment revealed critical role histone acetylation activity...
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent highly selective inhibitors effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing N-methyl group were designed directing toward conserved water pocket, two distinct binding conformations then observed. either...
CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort explore the potential therapeutic implications selectively targeting bromodomains, we set out identify a CBP/EP300 bromodomain inhibitor that was potent both vitro target engagement assays selective over other members family. Reported here is series cell-potent probes derived from fragment screening hit...
Inhibition of the bromodomain transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed vivo chemical tool 1 (GNE-272) for CBP that was moderately potent and selective over BRD4(1). In pursuit a more inhibitor, we used structure-based design. Constraining aniline into tetrahydroquinoline motif maintained potency increased selectivity 2-fold. Structure–activity relationship studies coupled with further design targeting LPF...
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target much recent interest in cancer and immune system regulation. A co-crystal structure ligand-efficient screening hit CBP guided initial design targeting LPF shelf, ZA loop, acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify more potent analogue. Optimization permeability microsomal stability subsequent improvement mouse hepatocyte afforded 59 (GNE-272,...
Myeloid-derived suppressor cells (MDSCs) are found in most cancer malignancies and support tumorigenesis by suppressing immunity promoting tumor growth. Here we identify the bromodomain (BRD) of CBP/EP300 as a critical regulator H3K27 acetylation (H3K27ac) MDSCs across promoters enhancers pro-tumorigenic target genes. In preclinical models, vivo administration CBP/EP300-BRD inhibitor (CBP/EP300-BRDi) alters intratumoral attenuates established growth immunocompetent tumor-bearing mice, well...
Full details of the total synthesis piericidin A1 and B1 its extension to preparation a series key analogues are described including ent-piericidin (ent-1), 4'-deshydroxypiericidin (58), 5'-desmethylpiericidin (73), 4'-deshydroxy-5'-desmethylpiericidin (75), corresponding 51, 59, 76, 77 bearing simplified farnesyl side chain. The evaluation these analogues, along with those derived from their further functionalizations, permitted scan structural features providing new insights into role...
A study of the structure−activity relationships (SAR) 2f (OL-135), a potent inhibitor fatty acid amide hydrolase (FAAH), is detailed, targeting 5-position oxazole. Examination series substituted benzene derivatives (12−14) revealed that optimal position for substitution was meta-position with selected members approaching or exceeding potency 2f. Concurrent these studies, effect on pyridine ring also examined. small, nonaromatic C5-substituents explored and Ki follows well-defined correlation...
A systematic study of the structure−activity relationships 2b (OL-135), a potent inhibitor fatty acid amide hydrolase (FAAH), is detailed targeting C2 acyl side chain. series aryl replacements or substituents for terminal phenyl group provided effective inhibitors (e.g., 5c, = 1-napthyl, Ki 2.6 nM), with 5hh (aryl 3-ClPh, 900 pM) being 5-fold more than 2b. Conformationally restricted chains were examined, and many exceptionally inhibitors, which 11j (ethylbiphenyl chain) was established to...
A series of α-ketooxazoles containing conformational constraints in the flexible C2 acyl side chain 2 (OL-135) and representative oxazole C5 substituents were prepared examined as inhibitors fatty acid amide hydrolase (FAAH). Exceptionally potent selective FAAH emerged from (e.g., 6, Ki = 200 260 pM for rat rhFAAH). With simple small substituents, each bearing a biphenylethyl, phenoxyphenethyl, or (phenoxymethyl)phenethyl was found to follow well-defined linear relationship between −log...
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many the beneficial effects exercise weight loss including lipid glucose trafficking. As such, enzyme long interest as target for treatment Type 2 Diabetes Mellitus. We describe optimization β1-selective, liver-targeted AMPK activators their evolution into systemic pan-activators capable acutely lowering mouse models. Identifying surrogates acid...
Regulatory T cells (Treg) are immunosuppressive and negatively impact response to cancer immunotherapies. CREB-binding protein (CBP) p300 closely related acetyltransferases transcriptional coactivators. Here, we evaluate the mechanisms by which CBP/p300 regulate Treg differentiation consequences of loss-of-function mutations in follicular lymphoma. Transcriptional epigenetic profiling identified a cascade transcription factors essential for differentiation. Mass spectrometry analysis showed...
The synthesis and examination of a systematic series 5-substituted 2-keto oxazoles as inhibitors fatty acid amide hydrolase (FAAH) defined fundamental substituent effect that led to the discovery with Ki's low 400 pM. intrinsic basis relationship (-log Ki vs sigmap), which relates Hammett sigmap constant substituent, magnitude (rho = 3.01), its predictive value (R2 0.91) suggest widespread applicability in studies beyond FAAH.
Bromodomains are acetyllysine recognition domains present in a variety of human proteins. also bind small molecules that compete with acetyllysine, and therefore bromodomains have been targets for drug discovery efforts. Highly potent selective ligands good cellular permeability proposed as chemical probes use exploring the functions many bromodomain We report here class such inhibitors targeting family VIII SMARCA2 (BRM) SMARCA4 (BRG1), PBRM1 (polybromo-1) 5. propose one example from this...
The biological function of bromodomains, epigenetic readers acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor the bromodomain cat eye syndrome chromosome region candidate 2 (CECR2). Screening internal medicinal chemistry collection led identification pyrrolopyridone chemical lead, subsequent structure-based drug design CECR2 (GNE-886) suitable for use as an in vitro tool compound.
AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid carbohydrate resulting from insulin resistance leads to hyperglycemia, the hallmark type 2 diabetes mellitus (T2DM). While pharmacological activation AMPK is anticipated improve these parameters, discovery selective, direct activators has proven challenging. We now describe hit-to-lead effort potent selective class benzimidazole-based...
The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind KAc region then building into LPF shelf. Herein, report "hybridization" variety KAc-binding fragments with tetrahydroquinoline scaffold makes optimal interactions shelf, imparting enhanced potency selectivity to hybridized ligand. To demonstrate utility our hybridization...
DFT and MMFF force field calculations for 2 (R = H) predict that two conformers dominate in water (≥95%) both sustain a geometry which the C−F H−N dipoles align oppositely near-planar arrangement. The 1H NMR spectra (D2O DMSO-d6) X-ray structure SO2NHEt) confirm predictions all essentials. A novel single-conformer system is proposed.