ACS Medicinal Chemistry Letters最新文献

CDK-based PROTAC therapeutics are a promising new approach in oncology. In this microperspective, we summarize the landscape of anticancer PROTAC development targeting the CDK family as of 2024. We discuss the applications and outcomes of computational screening, alternative degradation strategies, different linkers, SAR, and the use of new E3 ligases. Finally, we explore the potential to enhance pharmacokinetic properties through the incorporation of different linkers in heterobifunctional molecules.

Provided herein are novel substituted 1,1′-biphenyl compounds as glucagon receptor agonists, pharmaceutical compositions, use of such compounds in treating type 2 diabetes mellitus and obesity, and processes for preparing such compounds.

This study reports the synthesis, cytotoxic evaluation, and mechanistic insights of an amphiphilic triamino glycosylated antitumor ether lipid (GAEL). A series of aryl-substituted tricationic d-galacto-GAELs were synthesized to mimic cationic amphiphilic drug (CAD)-like structural characteristics. Among the series, the quinoline-bearing triamino GAEL (compound 17) exhibited the highest cytotoxicity in 2D cultures against drug-sensitive and drug-resistant ovarian, breast, pancreatic, liver, prostate, and brain cancer cells, completely eliminating all cells, whereas cisplatin and doxorubicin were less effective. GAEL 17 also demonstrated superior efficacy in an SK-OV-3 3D tumor spheroid model, fully disintegrating spheroids and inducing cell death at concentrations ≥25 μM. In contrast, doxorubicin reduced viability but did not eradicate spheroids at 50 μM, likely due to slower drug action or limited penetration over 48 h exposure. GAEL 17 retained caspase-independent, non-apoptotic cell death. LysoTracker assay indicated lysosomal disruption, while LipidTOX staining showed dose-dependent fluorescence, consistent with CAD-like lipid accumulation.

Biased signaling at G-protein-coupled receptors (GPCRs) enables pathway-selective modulation but remains challenging to characterize experimentally. We present OpioidBias, a machine learning tool for predicting G-protein versus β-arrestin bias in opioid ligands. A curated data set of opioid ligands was represented with >3800 descriptors from RDKit and Mordred, encompassing physicochemical, topological, and fingerprint-based features. Feature selection using Boruta and recursive feature elimination (RFE) guided the training of six classifiers. A random forest model incorporating combined RDKit and Mordred descriptors, fingerprints, and RFE showed the best performance and was further interpreted using feature analysis to identify molecular determinants of bias. OpioidBias is freely available (http://github.com/PGlab-NIPER/OpioidBias) to support biased ligand discovery across opioid pharmacology.

A focused small-molecule library was screened against extracellular Mycobacterium tuberculosis (Mtb) across four distinct carbon sources that mimic different metabolic states of the pathogen. This screen identified a novel tetrazol-2-yl-acetamide compound, sALT629 (P1), with potent intramacrophage activity (EC₅₀ = 1.5 μM). sALT629 showed broad-spectrum activities across all carbon sources, equipotent efficacy against drug-resistant Mtb, and activity against both slow-replicating and nonreplicating Mtb. Structure–activity relationship (SAR) studies optimized the potency and drug-like properties, leading to analogue P39 with improved intramacrophage activity (EC₅₀ = 0.68 μM) and pharmacokinetics (PK) properties. In mice, P39 achieved a plasma exposure of 58,754 ng/mL and maintained plasma concentrations above EC₅₀ for 16 h after a 20 mg/kg oral dose. Additionally, sALT629 showed good exposure and tolerability after repeated dosing for 4 days at 200 mg/kg once daily (QD) or 100 mg/kg twice daily (BID), indicating low toxicity liability and the potential for further development as an anti-tuberculosis (TB) drug candidate.

Provided herein are novel thio-substituted 1,3,5-triazine compounds as CX3CR1 modulators, pharmaceutical compositions, use of such compounds in treating cardiovascular diseases, and processes for preparing such compounds.

Provided herein are novel imidazopyridazine compounds as IL-17 inhibitors, pharmaceutical compositions, use of such compounds in treating inflammatory diseases, and processes for preparing such compounds.

Adenosine receptors (ARs) are G protein-coupled receptors involved in diverse physiological and pathological processes. Among them, the A₃ subtype (A₃AR) is an attractive therapeutic target due to its low basal expression and strong upregulation in inflamed or tumor tissues. Here, an A₁AR-derived xanthine scaffold was repurposed toward A₃AR antagonism by introducing a 1′-homologated 4′-truncated thiosugar at the N3 position. Structure–activity studies identified C8 substitution as the key determinant of subtype selectivity, while N1 groups modulated binding cooperatively. The optimized analogue 5p exhibited potent and selective A₃AR binding (K_i = 6.8 nM) with functional antagonism, showing an enhanced A₁/A₃ selectivity index (72) compared with that of the known xanthine-based A₃AR antagonist I-ABOPX (4.5). These findings demonstrate that thiosugar homologation effectively redirects xanthine scaffolds toward selective A₃AR antagonists and identify 5p as a promising lead compound.

Dual modulation of adenosine A_2A and A₃ receptors (ARs) is an emerging strategy for disorders involving receptor interplay. We designed and synthesized truncated 4′-thioadenosines bearing a C2–NH–R linker to enable dual A_2A/A₃ AR engagement. Structure–activity trends showed that aryl amine analogues tended to display affinity toward both A_2A and A₃ receptors, whereas aliphatic ones were inactive at both receptors. Ortho substitution in aryl amine analogues consistently enhanced binding affinity relative to meta or para substitution. Lead 4q (σ-morpholinophenyl) exhibited high affinity for hA_2AAR and hA₃AR (K_i = 15.0 ± 1.2 nM; 4.5 ± 0.5 nM). Computational modeling supported orthosteric binding at both receptors, and cAMP assays revealed inverse agonism at hA_2AAR (−19%) and antagonism at hA₃AR (69% inhibition of the NECA response). These findings suggest that the C2–NH–R-modified, truncated 4′-thioadenosine as a compact scaffold for A_2A/A₃ binding and highlight 4q as a dual ligand that may contribute to future AR ligand research.