ACS Medicinal Chemistry Letters最新文献

Provided herein are novel PARP7 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer and processes for preparing such compounds.

Astatine-211 (²¹¹At) is a promising alpha-emitting radionuclide for targeted alpha therapy (TAT), delivering high linear energy transfer (LET) and a short radiation range, making it ideal for cancer treatment while minimizing damage to surrounding healthy tissue. This viewpoint highlights recent advancements in the development of astatine-211 compounds for TAT, with a focus on the role of neighboring substituents in enhancing in vivo stability. By mitigating deastatination, these structural modifications improve radiopharmaceutical integrity, paving the way for more effective and clinically viable ²¹¹At-based radiopharmaceuticals.

A majority of drugs are small molecules that satisfy Lipinski’s Rule-of-Five (Ro5), but efforts to target topologically complex biomolecular interactions have reignited interest in nonconforming molecular therapeutics, dubbed “beyond Ro5 (bRo5)”. Broadly useful design principles for bRo5 molecules are few in number, although several studies have highlighted the benefit to bioavailability and proteolytic stability that can result from the introduction of a constraining ring into conformationally mobile peptides. Here we show that a linear oligomeric depsipeptide (OD) template can be leveraged to link size to permeability, while the corresponding cyclic oligomeric depsipeptide (COD) series is used to determine the impact of cyclization as an added conformational constraint. Unexpectedly, certain macrocycle sizes confer a greater benefit to permeability than others.

Provided herein are novel 1,6-naphthridine compounds as SMARCA2 inhibitors, pharmaceutical compositions, use of such compounds in treating non-small cell lung cancer and processes for preparing such compounds.

The M₂ muscarinic acetylcholine receptor (M₂R) is a G protein-coupled receptor involved in regulating cardiovascular functions and mediation of central muscarinic effects, such as movement, temperature control, and antinociceptive responses. Molecular probes targeting this receptor are therefore important in exploring its pathophysiological role at a molecular level. Herein, we report the design, synthesis, and evaluation of a new fluorescent probe for M₂R based on an anthranilamide ligand. In radioligand binding experiments, the presented Oregon Green 488-labeled conjugate (33) exhibited high M₂R affinity (K_i = 2.4 nM), a moderate preference for the M₂R over the M₄ receptor, and excellent to pronounced M₂R selectivity compared to the M₁, M₃, and M₅ receptors. The utility of the probe was demonstrated in confocal, two-photon, and stimulated emission depletion nanoscopy (STED) imaging to specifically label the receptors in human embryonic kidney (HEK) 293T cells. These properties suggest that our probe may be utilized in advanced microscopy to study the pharmacology of the M₂R.

The phospholipid sensing transcription factor liver receptor homologue 1 (LRH-1) participates in the transcriptional regulation of metabolic balance and inflammation in liver, pancreas, and other tissues. It is an emerging target for metabolic dysfunction, fatty liver disease, and cancer, but LRH-1 modulators are rare and lack drug-like properties. We discovered new LRH-1 ligands with improved physicochemical features in a fragment-based approach and optimized a venlafaxine-related lead for LRH-1 activation. Despite a strict structure–activity relationship, systematic structural variation resulted in a new LRH-1 agonist scaffold with strong activation efficacy, validated direct and cellular target engagement, and anti-inflammatory and ER-stress-resolving properties in functional cellular settings.

Most ligands for the Von Hippel–Lindau tumor suppressor (VHL) bind at the HIF-1α binding site. Ligands that bind to allosteric sites on VHL could be highly valuable for the field of protein degradation, therefore, a covalent hit identification campaign was run targeting Cys77 on VHL. Hit 2 bound selectively to Cys77 on VHL and did not alkylate the reactive Cys89 on Elongin B. It showed time- and concentration-dependent labeling, with a k_inact/K_I of 0.30 M^–1 s^–1, and does not affect binding at the HIF-1α site. This hit ligand was optimized to afford compound 15 which showed improved potency and labeling of VHL. An X-ray structure of a close analogue was determined revealing the compound binding in a shallow groove on the surface of VHL. These are the first small molecules that bind covalently to an allosteric site on VHL and provide a suitable starting point for further optimization.

Psychedelics and AI modulate cognitive frameworks, disrupt rigid thought patterns, and enhance neuroplasticity, offering therapeutic potential for depression, PTSD, and addiction. Relaxing neural filters reveal altered states of consciousness, challenging perceptions of reality. This Viewpoint explores their neurobiological mechanisms and AI’s role in augmenting psychiatric treatments.

This highlight describes a series of novel 6-aryl isoindolin-1-one derivatives as negative allosteric modulators (NAMs) of the metabotropic glutamate receptor 2 (mGluR₂). The chemical synthesis, selectivity over mGluR₃, and pharmaceutical compositions of those compounds are disclosed.

The ability to adopt folded conformations that have a low solvent-accessible 3D polar surface area has been found to be important for PROTACs to display a high passive cell permeability. We have studied two VHL PROTACs that differ only by the replacement of two methylene groups in the linker by oxygen atoms but that displayed vast differences in their cell permeability. MD simulations and NMR spectroscopy revealed an unexpected, environment-dependent conformational behavior for the low-permeability PROTAC that has an alkyl linker. Hydrophobic interactions enforced extended and polar conformations for this PROTAC in nonpolar media, explaining its low cell permeability. In water, hydrophobic collapse around the linker led to folded and less polar conformations. In contrast, the highly permeable PROTAC having a PEG linker adopted conformations of similar shapes and polarities in polar and nonpolar environments.