ACS Medicinal Chemistry Letters最新文献

Recent advancements in the therapeutic use of psychedelic compounds, particularly 5-MeO-DMT and DMT, have demonstrated significant potential in treating various mental health disorders. This Patent Highlight evaluates findings from multiple recent patents that explore novel applications of these compounds, including their use in severe psychiatric conditions such as depression, anxiety, and trauma-related disorders. The patents reveal innovative strategies, such as combining 5-MeO-DMT with mood preparation agents to enhance safety and efficacy, developing DMT prodrugs for improved pharmacokinetics, and targeting specific populations like breastfeeding mothers with tailored psychedelic therapies. These advancements offer new hope for patients with treatment-resistant mental disorders, highlighting the evolving role of psychedelics in mental health care.

Psilocybin, a naturally occurring psychedelic compound, has recently emerged as a promising therapeutic agent for mental health. This Patent Highlight explores the innovative approaches to harnessing psilocybin's potential across various contexts. These include clinical trials targeting severe psychiatric conditions, the integration of low-dose psilocybin into dietary products to promote general mental well-being, and the personalization of psilocybin dosing for optimal treatment of depression and anxiety. These advancements demonstrate psilocybin's versatility and potential to reshape conventional mental health treatment paradigms, mainly through personalized medicine and accessible wellness applications.

Herein, we performed a virtual screening study to discover new scaffolds for small molecule-based ligands of the immune checkpoint lymphocyte-activation gene 3 (LAG-3). Molecular dynamics (MD) simulations using the LAG-3 structure revealed two putative binding sites for small molecules: the antibody interface and the lipophilic canyon. A 3D pharmacophore screening resulted in the identification of potential ligands for these binding sites and afforded a library of 25 compounds. We then evaluated the screening hits for LAG-3 binding via microscale thermophoresis (MST) and surface plasmon resonance (SPR). Our biophysical screening identified two binders with K _D values in the low micromolar range, compounds 3 (antibody interface) and 25 (lipophilic canyon). Furthermore, we investigated the ability of LAG-3 hits to engage LAG-3 on a cellular level using a cellular thermal shift assay (CETSA). In summary, compound 3 shows potential as a lead but is not yet a development candidate.

In the rapidly evolving field of oncology, the need for innovative therapeutic strategies is more pressing than ever. Many cancers, especially those driven by gene mutations like KRAS, remain challenging to treat. Traditional approaches, which often rely on small-molecule inhibitors, face significant limitations, particularly in addressing “undruggable” targets or delivering large therapeutic molecules across cellular membranes. As highlighted by four essential patents, the recent advancements in Proteolysis Targeting Chimeras (PROTACs) and intracellular delivery systems offer novel and promising strategies to overcome these challenges.

This Patent Highlight explores recent cancer treatment and monitoring advancements, focusing on selective KRAS inhibitors targeting mutations like G12C and G12D alongside germline epitope burden analysis. These innovations offer enhanced therapeutic precision and personalized monitoring, improving the prediction of cancer relapse and tailoring treatment strategies to individual patient profiles, significantly advancing the field of precision oncology.

Inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) facilitates potent antiangiogenic and anticancer responses. In this regard, the development of effective pharmacophores, i.e., quinoline-based triazole derivatives 6a–j, by a one-pot telescopic approach is our focus. Among all of them, 6f, possessing amide and cyanide substituents, displayed the highest binding ability with VEGFR-2, having high affinity of −8.9 kcal/mol. Further, 6f and 6g (containing amide and bromo groups) exhibited a wide spectrum of anticancer activities due to the presence of active oxidative stress inducers, with cytotoxicity values of 10 ± 0.2 and 12 ± 0.6 μM, respectively. Apoptosis analysis demonstrated the involvement of 6f and 6g in mitochondrial damage and the loss of mitochondrial membrane potential (ΔΨ_m). Intercellular localization of 6f/6g in MCF-7 revealed the presence of 6g in the cytoplasm along with an increase in ROS production and a reduction in MMP, proving the ability of 6g to target mitochondria.

Psilocybin, a naturally occurring psychedelic compound, has recently emerged as a promising therapeutic agent for mental health. This Patent Highlight explores the innovative approaches to harnessing psilocybin’s potential across various contexts. These include clinical trials targeting severe psychiatric conditions, the integration of low-dose psilocybin into dietary products to promote general mental well-being, and the personalization of psilocybin dosing for optimal treatment of depression and anxiety. These advancements demonstrate psilocybin’s versatility and potential to reshape conventional mental health treatment paradigms, mainly through personalized medicine and accessible wellness applications.

Targeted protein degradation has been emerging as a promising strategy for drug design and a useful tool for the research of intracellular protein function by specifically downregulating the protein level via promoted degradation. Aside from proteolysis targeting chimeras (PROTAC) that utilize a specific E3 ligase ligand as a tag to recruit polyubiquitin onto the targeted protein and subsequently induce degradation, Boc₃Arg was also reported an efficient tag to induce degradation through directly localizing the protein to the 20S proteasome. Based on the similarity of Boc₂Lys and Boc₃Arg, we identified that Boc₂Lys also efficiently induced targeted protein degradation, taking glutathione S-transferase as an example. We found that Boc₂Lys-linked ethacrynic acid was able to dose-dependently downregulate the target protein in a mechanism distinct to Boc₃Arg.

Provided herein are novel pyrazolopyridine and triazolopyridine derivatives as DGAT2 inhibitors, pharmaceutical compositions, use of such compounds in treating multiple diseases, and processes for preparing such compounds.

Targeted protein degradation has been emerging as a promising strategy for drug design and a useful tool for the research of intracellular protein function by specifically downregulating the protein level via promoted degradation. Aside from proteolysis targeting chimeras (PROTAC) that utilize a specific E3 ligase ligand as a tag to recruit polyubiquitin onto the targeted protein and subsequently induce degradation, Boc₃Arg was also reported an efficient tag to induce degradation through directly localizing the protein to the 20S proteasome. Based on the similarity of Boc₂Lys and Boc₃Arg, we identified that Boc₂Lys also efficiently induced targeted protein degradation, taking glutathione S-transferase as an example. We found that Boc₂Lys-linked ethacrynic acid was able to dose-dependently downregulate the target protein in a mechanism distinct to Boc₃Arg.