ACS Medicinal Chemistry Letters最新文献

Provided herein are novel imidazo[4,5-c]pyridine compounds as TLR7 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Provided herein are novel imidazo[4,5-c]pyridine compounds as TLR7 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Provided herein are novel pyridine derivatives as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating psychiatric disorders, and processes for preparing such compounds.

New ubiquitin ligase (E3) ligands are crucial for developing proteolysis-targeting chimeras (PROTACs) to induce the degradation of a target protein. In this study, we developed a PROTAC using the antipsychotic drug clozapine as a new E3 ligand. First, a clozapine PROTAC targeting a model target HaloTag protein (Halo-PEG-Clozapine) was synthesized, and the PROTAC induced degradation of the HaloTag-fused protein in a cell culture system. Another clozapine PROTAC targeting the cancer therapeutic target estrogen receptor α (ERα) (Tamoxifen-PEG-Clozapine) was synthesized and induced degradation of the ERα protein in MCF-7 breast cancer cells. Experiments with inhibitors and siRNAs showed that Tamoxifen-PEG-Clozapine degraded ERα via a ubiquitin-proteasome system that uses the ubiquitin protein ligase E3 component N-recognin 5. These results indicate that clozapine is a promising E3 ligand that may expand the molecular design of PROTACs, contributing to the advancement of drug discovery by facilitating the degradation of disease-related proteins.

Provided herein are novel 6-substituted-3-phenylisoindolin-1-ones as Cbl-b inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Bromodomain adjacent to zinc finger 2A and 2B (BAZ2A and BAZ2B) are homologous proteins that serve as regulatory subunits in different initiation switch complexes. Despite their structural similarity, BAZ2A/B seem to play different roles in disease development. However, reported BAZ2A/B inhibitors bind similarly to both homologues. Here we report the discovery of dBAZ2 and dBAZ2B, first-in-class Proteolysis Targeting Chimeras (PROTACs) degrading BAZ2A/B and BAZ2B, respectively. dBAZ2 induces BAZ2A/B degradation with a D _max ≥ 97% (BAZ2A_DC₅₀ = 180 nM; BAZ2B_DC₅₀ = 250 nM), while dBAZ2B selectively degrades BAZ2B with a DC₅₀ = 19 nM and D _max ≥ 97%. Degradation by dBAZ2 and dBAZ2B is almost complete within 2 h, is maintained for at least 3 days, and occurs in PC3 and MM1S cells, demonstrating the potential of these compounds as chemical probes to decipher the distinct biological functions of BAZ2A/B.

Bromodomain adjacent to zinc finger 2A and 2B (BAZ2A and BAZ2B) are homologous proteins that serve as regulatory subunits in different initiation switch complexes. Despite their structural similarity, BAZ2A/B seem to play different roles in disease development. However, reported BAZ2A/B inhibitors bind similarly to both homologues. Here we report the discovery of dBAZ2 and dBAZ2B, first-in-class Proteolysis Targeting Chimeras (PROTACs) degrading BAZ2A/B and BAZ2B, respectively. dBAZ2 induces BAZ2A/B degradation with a D_max ≥ 97% (BAZ2A_DC₅₀ = 180 nM; BAZ2B_DC₅₀ = 250 nM), while dBAZ2B selectively degrades BAZ2B with a DC₅₀ = 19 nM and D_max ≥ 97%. Degradation by dBAZ2 and dBAZ2B is almost complete within 2 h, is maintained for at least 3 days, and occurs in PC3 and MM1S cells, demonstrating the potential of these compounds as chemical probes to decipher the distinct biological functions of BAZ2A/B.

We report the first structure–activity studies of arylidene–indolinone compound GW5074, which was reported as a ligand of autophagy-related protein LC3B. The literature has conflicting information on the binding affinity of this compound, and there is some debate regarding its use as a component of autophagy-dependent degrader compounds. We developed an AlphaScreen assay to measure competitive inhibition of the binding of known peptide ligands to LC3B and its paralog GABARAP. Eighteen analogs were synthesized and tested against both proteins. Inhibitory potencies were found to be in the mid- to high-micromolar range. 2D-NMR data revealed the binding site on GABARAP as hydrophobic pocket 1, where native peptide ligands bind with an aromatic side chain. Our results suggest that GW5074 binds LC3B and GABARAP with micromolar affinity. These affinities could support further exploration in targeted protein degradation, but only if off-target effects and poor solubility can be appropriately addressed.

The invention in this patent describes novel 5H-imidazo[1,5-b][1,2,4]triazole compounds, including radiolabeled derivatives, designed to target alpha-synuclein (α-syn). These compounds demonstrate potential as positron emission tomography (PET) radioligands for diagnosing α-syn-associated brain diseases, including Parkinson’s disease.

[This corrects the article DOI: 10.1021/acsmedchemlett.4c00450.].