Category: 1799973-82-2

Davies, Thomas G. published the artcileMonoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery, COA of Formula: C8H8BrN3O, the publication is Journal of Medicinal Chemistry (2016), 59(8), 3991-4006, database is CAplus and MEDLINE.

KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacol. intervention has focused on mols. that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallog. screening identified three distinct “hot-spots” for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to mols. with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound (I) which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chem. probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.

Journal of Medicinal Chemistry published new progress about 1799973-82-2. 1799973-82-2 belongs to triazoles, auxiliary class Other Aromatic Heterocyclic,Bromide,Ether, name is 5-Bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole, and the molecular formula is C8H8BrN3O, COA of Formula: C8H8BrN3O.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Pallesen, Jakob S. published the artcileDeconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds, SDS of cas: 1799973-82-2, the publication is Journal of Medicinal Chemistry (2021), 64(8), 4623-4661, database is CAplus and MEDLINE.

Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-mol. Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallog. to bind in the Keap1 Kelch binding pocket. Two hits were merged into pyrazole I with a 220-380-fold stronger affinity (K_i = 16μM) relative to the parent fragments. Systematic optimization resulted in several novel analogs with K_i values of 0.04-0.5μM, binding modes determined by X-ray crystallog., and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.

Journal of Medicinal Chemistry published new progress about 1799973-82-2. 1799973-82-2 belongs to triazoles, auxiliary class Other Aromatic Heterocyclic,Bromide,Ether, name is 5-Bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole, and the molecular formula is C8H8BrN3O, SDS of cas: 1799973-82-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Tran, Kim T. published the artcileA Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity, HPLC of Formula: 1799973-82-2, the publication is Journal of Medicinal Chemistry (2019), 62(17), 8028-8052, database is CAplus and MEDLINE.

Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-mol. Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochem. properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacol. probes or starting points for developing CNS-active Keap1 inhibitors.

Journal of Medicinal Chemistry published new progress about 1799973-82-2. 1799973-82-2 belongs to triazoles, auxiliary class Other Aromatic Heterocyclic,Bromide,Ether, name is 5-Bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole, and the molecular formula is C4H3Cl2N3, HPLC of Formula: 1799973-82-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics