ACS Medicinal Chemistry Letters最新文献

Recent patent disclosures highlight a conceptual shift in drug discovery, integrating targeted protein degradation with functional precision oncology. IRAK-M and IRAK4 degraders exemplify how innate immune signaling can be rewired through selective protein removal, while patient-derived microcancer platforms provide a decision framework for rationally deploying such agents. Together, these inventions redefine how molecular precision and biological context converge to guide translational success.

Recent patent disclosures from Gilead Sciences reveal a coordinated, multimodal strategy to control STAT6 signaling therapeutically. Small-molecule modulators provide tunable, tissue-focused pathway attenuation, while heterobifunctional degraders enable more profound and potentially more durable suppression. Together, these inventions define STAT6 as a context-sensitive target whose optimal intervention depends on disease biology, exposure, and required depth of pathway control.

Recent patent disclosures illustrate how modern medicinal chemistry advances by aligning biological insight with chemical modality, formulation rigor, and molecular measurement. Targeted protein degradation to overcome resistance, solid-state engineering to ensure sustained pathway suppression, and single-cell genomic profiling to resolve metastatic biology together demonstrate how therapeutic impact emerges when perturbation, delivery, and biological observability are coherently integrated.

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is a promising therapeutic target for pancreatic ductal adenocarcinoma (PDAC). Herein, we developed an integrated AI and structure-based pipeline featuring a Serial PNA-Transformer graph neural network, which achieved a test AUC of 0.8901. Multistage screening of 21,738 compounds prioritized 232 candidates across 10 chemical clusters. Enzymatic assays confirmed three hits with IC₅₀ values <500 nM; notably, CX-6258 (IC₅₀ = 473.7 nM) exhibited potent antiproliferative activity in MIA PaCa-2 and Panc-1 cell lines with low micromolar potencies (IC₅₀ = 0.679 and 1.148 μM, respectively). Selectivity profiling confirmed the potency of CX-6258 against DYRK1A/B with a favorable window over other CMGC kinases. Crucially, siRNA-mediated knockdown and overexpression assays demonstrated that its cytotoxicity is strictly DYRK1A-dependent. Molecular dynamics revealed a stable binding mode characterized by a unique Arg250-mediated electrostatic driving force. These findings underscore the utility of our AI-driven framework in accelerating the identification and mechanistic validation of potent therapeutic leads.

Human secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) catalyze the conversion of protein N-terminal glutamine into pyroglutamate (pE), a modification implicated in human diseases including cancer. Small-molecule inhibitors targeting sQC/gQC represent a promising therapeutic strategy. Here, we report a series of benzyl-5-methyl-1H-imidazole derivatives as inhibitors of sQC/gQC. Through structural optimization, we identified CL121, a nanomolar potent inhibitor of both enzymes. Thermal shift assays revealed that CL121 enhances the thermal stability of both sQC (ΔT_m = 5.9 °C) and gQC (ΔT_m = 6.0 °C), indicating strong binding interactions. Cellular assays revealed that CL121 substantially reduced the level of pE-CD47 modification on the surface of MDA-MB-231 and KYSE30 cells. Furthermore, CL121 exhibited antitumor activity in a mouse xenograft tumor model. The results highlight the potential of CL121 as a lead compound for developing drugs targeting sQC/gQC-mediated diseases.

Despite recent interest in N-trifluoromethyl azoles, N-α,α-difluoroalkyl azoles [(azole)N–CF₂R] remain understudied and underutilized in medicinal chemistry. To address this deficiency, we have conducted a comparative study of medicinally relevant properties for a series of (azole)N–CF₂R and their nonfluorinated matched molecular pairs (MMPs) that revealed fluorine-induced reductions in azole pK_a, hydrophilicity, experimental polar surface area, and metabolic oxidation of a labile vicinal position. Additionally, computational analysis supports the fluorine-induced suppression of metabolic aliphatic oxidation but suggests a limited impact of fluorination on conformational preferences within MMPs. Along with a newly provided synthetic method to install such a substructure, this information will facilitate rational incorporation of (azole)N–CF₂R groups in drug optimization campaigns.

Unbound volume of distribution is often treated as an intrinsic, species-invariant property. However, mechanistic analysis demonstrates that it is influenced by plasma protein binding, particularly when plasma and tissue binding are coupled through shared binding components and their relative compartmental distribution. Evidence across rat strains suggests that plasma protein binding significantly modulates half-life and hepatic extraction, thereby impacting in vivo efficacy. These insights argue for revisiting common cross-species scaling practices and for considering plasma protein binding as an explicit design parameter.

Colorectal cancer remains a leading cause of cancer-related mortality. Although KRAS^G12C inhibitors have been approved for the treatment of multiple cancers, their clinical efficacy is often limited by KRAS reactivation. SOS1, a key guanine nucleotide exchange factor involved in KRAS activation and implicated in various malignancies, including colorectal and oral cancers, represents an attractive therapeutic target. In this study, fragment-based virtual screening targeting the Asn879 pocket of SOS1 was performed using the DrugBank database and an in-house chemical library, followed by structure-based optimization and structure–activity relationship analysis. Twenty derivatives were synthesized, among which compound 20, featuring a 6-methyl-1H-imidazo[4,5-g]quinazoline scaffold, exhibited the most potent inhibition of the SOS1::KRAS^G12C interaction (IC₅₀ = 4.11 nM). Compound 20 also demonstrated significant antiproliferative activity against DLD-1 CRC cells by inducing apoptosis and G0/G1 cell-cycle arrest. These results identify compound 20 as a promising lead for SOS1-targeted therapy.