ACS Medicinal Chemistry Letters最新文献

Recent patent disclosures reveal convergent strategies to modulate IL-17-driven pathology through complementary chemical and delivery modalities. Acidic small-molecule inhibitors, PEGylated derivatives, and antibody-functionalized lipid nanoparticles collectively address potency, exposure, and immune context. Together, these approaches outline an integrated framework for treating inflammatory diseases and immunosuppressive tumor microenvironments.

Cytochalasans are actin polymerization inhibitors with potent migrastatic activity, but their potential therapeutic use is limited by their cytotoxicity. Here, we describe a modular late-stage approach that introduces unprecedented 10-phenoxy substituents into the cytochalasan scaffold via a Mitsunobu reaction. A series of ten 10-phenoxycytochalasan analogues was synthesized and evaluated for actin polymerization inhibition, migrastatic activity, and cytotoxicity (BLM, MRC-5, and HaCaT). At 10 μM concentration, several 7-hydroxy-10-phenoxycytochalasans (12a,d–g) significantly inhibited actin polymerization in vitro and showed migrastatic effects in a spheroid invasion assay. Para-substituents of the phenoxy group modulated cytotoxicity without compromising actin polymerization inhibition or migrastatic activity. In contrast, lipophilic ortho-substituents predicted by molecular docking to enhance actin binding failed to manifest migrastatic activity, underscoring the limitations of the molecular docking with this type of compounds. These findings demonstrate that migrastatic and cytotoxic effects can be decoupled in cytochalasan analogues and highlight 10-phenoxy substitution as a promising strategy toward noncytotoxic migrastatic agents.

Provided herein are novel compounds as PKC-theta inhibitors, pharmaceutical compositions, use of such compounds in treating autoimmune or inflammatory diseases, and processes for preparing such compounds.

Human DNA polymerase θ (Polθ) is essential for microhomology-mediated end-joining (MMEJ) and represents a therapeutic vulnerability in homologous recombination (HR)-deficient cancers. Although reversible inhibitors of Polθ have advanced into clinical development, covalent chemical probes remain unexplored. Analysis of a previously described structure of the reversible inhibitor compound 37 bound to Polθ identified Cys2411 as an accessible residue 7.4 Å adjacent to the inhibitor binding site. Guided by X-ray crystallographic studies, we designed compound 29 to reduce the separating distance between inhibitor and Cys2411 to 4.7 Å and then synthesized RP-4029 by incorporating a vinyl sulfone electrophile. Functional studies revealed efficient covalent linkage to Cys2411 (K_inact = 11.6 s^–1), while a high-resolution (2.0 Å) cocrystal structure validated the design strategy. These findings establish Cys2411 as a privileged site for covalent inhibitor development and provide a highly potent, selective chemical probe useful for investigating Polθ biology.

Provided herein are novel compounds as TIPARP inhibitors, pharmaceutical compositions, use of such compounds in treating head and neck squamous cell carcinoma (HNSCC), and processes for preparing such compounds.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose loss-of-function variants increase Alzheimer’s disease (AD) risk. While antibody-based agonists have shown promise, their translation is hindered by poor brain penetration and high cost. Here, we report the discovery and optimization of small-molecule TREM2 agonists through an AI-assisted virtual screening strategy. Deep docking of over five million purchasable compounds identified a structurally novel hit, T2K-014, which engaged TREM2 with modest affinity. A SAR-by-catalog campaign led to the identification of T2M-010 as a potent binder. T2M-010 demonstrated favorable in vitro PK properties, including high solubility, passive BBB permeability, moderate metabolic stability, and minimal safety liabilities. Functionally, T2M-010 activated receptor-proximal signaling, inducing SYK phosphorylation in TREM2-expressing cells, and promoted microglial phagocytosis. Together, these findings establish T2M-010 as the most potent small-molecule TREM2 binder reported to date capable of driving protective microglial responses relevant to AD.

Provided herein are novel acrylamide derivatives as mitochondrial permeability transition pore (mPTP) inhibitors, pharmaceutical compositions, use of such compounds in treating neurodegenerative diseases, and processes for preparing such compounds.

Acyl glucuronides are common metabolites of carboxylic acids. They can be reactive and cause adverse events. The acyl glucuronide metabolite of delta-9-tetrahydrocannabinol (THC) is abundant in humans after THC consumption but acyl glucuronide formation from the cannabidiol (CBD) metabolite 7-carboxy-cannabidiol (7-COOH-CBD) has not been previously described. Here, we identified and characterized both acyl and phenolic glucuronides of 7-COOH-CBD formed in human liver, kidney, and intestinal microsomes. The 7-COOH-CBD-acyl-glucuronide was mostly formed by UGT1A1 and UGT1A3, while the 7-COOH-CBD-phenolic-glucuronide was formed by UGT1A9. 7-COOH-CBD-acyl-glucuronide formation was also detected in vivo in mice. 7-COOH-CBD-acyl-glucuronide showed extensive acyl migration while 11-COOH-THC-glucuronide did not. Human serum albumin enhanced migration, while liver fatty acid binding protein (FABP1) protected against 7-COOH-CBD-acyl-glucuronide migration. When corrected for unbound fraction, FABP1 increased 7-COOH-CBD glucuronidation efficiency. These findings suggest that 7-COOH-CBD-acyl-glucuronide is a metabolite of CBD in humans and may play a role in CBD related liver toxicity.

Casein kinase 1α (CK1α) is a serine/threonine kinase that plays a pivotal role in regulating p53 and other critical signaling pathways and is intimately involved in tumor initiation and progression. Inhibition of CK1α has been demonstrated to be a promising therapeutic strategy for certain types of cancers such as acute myeloid leukemia (AML). In this study, we designed and synthesized a series of novel CK1α inhibitors bearing a 7H-pyrrolo[2,3-d]pyrimidine scaffold. The structure–activity relationship was systematically summarized, and notably, compound 7a exhibited potent inhibitory activity against CK1α with an IC₅₀ of 10.96 nM, representing a 9-fold increase in potency as compared to BTX-A51, the only CK1α inhibitor currently in clinical development. Additionally, compound 7a displayed favorable selectivity across a panel of kinases. It also dose-dependently stabilized p53 protein and effectively inhibited the growth of MV4-11 cells. Further optimization of 7a may provide promising CK1α inhibitors with desirable drug-like properties for cancer treatment.