ACS Medicinal Chemistry Letters最新文献

A hallmark of most known small-molecule orthosteric kinase inhibitors is hydrogen-bonding to the hinge-region of the kinase to mimic the hinge interaction of adenine. Herein we report our studies on deviation from canonical hinge-binders in the context of IRAK4 inhibitors. Small-molecule inhibitors of IRAK4 have generated interest as potential treatments for inflammatory diseases. Notably, in our discovery efforts we identified pyridinyl-thiadiazoles as noncanonical hinge-binders. X-ray structural evidence supports that the thiadiazole moiety engages in a rare intermolecular noncovalent sulfur–oxygen interaction. This thiadiazole series, exemplified by compounds 19 and 22, has shown promise for potent, selective, orally bioavailable IRAK4 inhibitors.

Emerging psychedelic therapeutics increasingly rely on mechanistic precision, receptor selectivity, and pharmacokinetic control. Recent inventions introduce simplified iboga analogs with tunable polypharmacology, real-time EEG biomarkers that individualize psilocybin dosing, and standardized harmine–DMT ratios with high bioavailability. Together, these innovations form a coherent framework for safer, more reliable, and clinically actionable psychedelic medicines.

Three recent inventions highlight complementary advances in oncology: macrocyclic multitarget ALK inhibitors for resistant NSCLC, impedance-based cfDNA staging as a label-free diagnostic, and transcriptome-driven prediction of KRAS inhibitor response. Together, they illustrate an emerging paradigm in precision oncology that integrates molecular design, biophysical classification, and computational phenotyping to refine therapeutic selection and improve clinical outcomes.

Provided herein are novel compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating mental illness or CNS disorders, and processes for preparing such compounds.

New inventions introduce complementary advances across neuropsychiatric therapeutics: a blood-based gene-expression diagnostic centered on FOXG1 for objective PTSD detection; benzocyclobutenyl-methylamine modulators that normalize neuronal hyperexcitability; and templated-carrier sublingual 5-MeO-DMT formulations enabling controlled, nonhallucinogenic neuroplasticity. Together, these approaches form a convergent framework linking molecular diagnostics, targeted circuit modulation, and scalable affective therapeutics.

Recent innovations in ADC design and innate immune modulation reveal complementary therapeutic strategies for cancer and inflammatory diseases. Novel hydrophilic multivalent linkers enable very high drug-to-antibody ratios and dual-payload ADCs, while modulation of MDAS, TLR7, TLR5, and STING pathways induces p16⁺ immune subsets that promote disease tolerance. Together, these inventions highlight convergent mechanisms for improving efficacy, resilience, and therapeutic durability.

Cardiac hypertrophy poses a clinical challenge in heart failure progression with limited therapeutic options to reverse the process of pathological remodeling. We present a high-throughput phenotypic screening assay designed to support lead optimization from novel approaches. A mixed cell culture from neonatal rat hearts was established, allowing simultaneous assessment of cardiomyocytes and noncardiomyocytes within a shared physiologically relevant microenvironment. Customized CellProfiler-based image analysis extracted multiparametric morphological data that was merged in a “Hypertrophy Score” metric for quantitative analyses. The assay was applied to investigate G protein-coupled receptor kinase 5 (GRK5) as a promising target in cardiac hypertrophy. Structure–activity and −property relationships from a focused GRK5 inhibitor collection revealed a negative influence on cellular efficacy by lipophilic and covalently reactive compounds. Correlating biochemical with cellular data eliminated GRK6 as a common off-target concern and underlined the value of potent GRK5 versus GRK2 inhibition. Diastereomers 4a/b were identified as valuable chemical probes.

This patent describes novel spiro-ureas as a novel class of monoacylglycerol lipase (MAGL) inhibitors. It provides details on the novel substituted spiro-ureas, pharmaceutical composition, and therapeutic applications for diseases associated with MAGL dysregulation.

In pursuit of potent, efficacious influenza inhibitors with novel mechanisms, we replaced the 7-azaindole core of the PB2 inhibitor pimodivir (VX-787/JNJ872) with a 7-fluoro-substituted indazole to mitigate CYP3A- and aldehyde oxidase-mediated metabolism by lowering lipophilicity and blocking the metabolic soft spot. We further introduced a cyclopropyl-fused ring onto the bridged bicyclo[2.2.2]octane to retain potency while reducing glucuronidation. This design converged in compound 3, where the indazole scaffold and fused cyclopropyl ring acted synergistically to improve the potency and pharmacokinetic properties. In a lethal influenza mouse challenge model, compound 3 achieved approximately a 7-fold reduction in the effective dose compared with pimodivir. It also showed significantly improved activity against selected influenza A strains versus pimodivir, highlighting its potential as a differentiated PB2 inhibitor.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is an enzyme that plays a critical role in regulating cell growth, development, and survival. This patent showcases the synthesis and pharmaceutical compositions of novel PTPN2 inhibitors and their applications in the prevention, treatment, and amelioration of cancers.