A5080329100- Protein Degradation and Inhibitors
- Monoclonal and Polyclonal Antibodies Research
- Multiple Myeloma Research and Treatments
- Retinoids in leukemia and cellular processes
- Magnetism in coordination complexes
- Drug Transport and Resistance Mechanisms
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- Protein purification and stability
- HER2/EGFR in Cancer Research
- Advanced biosensing and bioanalysis techniques
- Synthesis and Characterization of Heterocyclic Compounds
- Advanced Biosensing Techniques and Applications
- Peroxisome Proliferator-Activated Receptors
- Chemical Synthesis and Analysis
- Molecular Sensors and Ion Detection
- Cancer therapeutics and mechanisms
- Analytical Chemistry and Sensors
- Vanadium and Halogenation Chemistry
- Medical Imaging and Pathology Studies
- Histone Deacetylase Inhibitors Research
- Click Chemistry and Applications
- Cellular transport and secretion
- HIV/AIDS drug development and treatment
- Ubiquitin and proteasome pathways
Constellation Pharmaceuticals (United States)
2016
Genentech
2013-2014
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,...
A minor structural change to tertiary sulfonamide RORc ligands led distinct mechanisms of action. Co-crystal structures two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving in our biochemical assay also gave rise an increased production IL-17 human PBMCs whereas significant suppression under the same conditions. The most...
Agonism of members the tumor necrosis factor receptor superfamily (TNFRSF) with monoclonal antibodies is high therapeutic interest due to their role in immune regulation and cell proliferation. A major hurdle for pharmacologic activation this class requirement high-order clustering, a mechanism that imposes reliance vivo on Fc receptor-mediated crosslinking. This extrinsic dependence represents potential limitation virtually entire pipeline agonist TNFRSF antibody drugs, which none have thus...
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...
Antibodies are fundamental effectors of humoral immunity, and have become a highly successful class therapeutics. There is increasing evidence that antibodies utilize transient homotypic interactions to enhance function, elucidation such can provide insights into their biology new opportunities for optimization as drugs. Yet the transitory nature weak makes them difficult investigate. Capitalizing on rich structural data high conservation, we characterized all ways antibody fragment...
Abstract Antibodies are fundamental effectors of humoral immunity, and have become a highly successful class therapeutics. There is increasing evidence that antibodies utilize transient homotypic interactions to enhance function, elucidation such can provide insights into their biology new opportunities for optimization as drugs. Yet the transitory nature weak makes them difficult investigate. Capitalizing on rich structural data high conservation, we characterized all ways antibody Fab...