Kaneko H, Nagatoishi S, Tsumoto K
… +2 more, Ando T, Shiroishi M
ACS Med Chem Lett
· 2026 Feb · PMID 41704352
·
Full text
Understanding the thermodynamic basis of ligand recognition by G-protein-coupled receptors (GPCRs) is crucial for rational drug design. Here, we directly characterized the binding thermodynamics of the histamine H recept...Understanding the thermodynamic basis of ligand recognition by G-protein-coupled receptors (GPCRs) is crucial for rational drug design. Here, we directly characterized the binding thermodynamics of the histamine H receptor (HR) interacting with the geometric isomers of doxepin using isothermal titration calorimetry combined with molecular dynamics (MD) simulations. The -isomer binding to HR_WT exhibited a larger enthalpic gain but a greater entropic loss than the -isomer, whereas these differences were diminished in the T112V mutant. Cluster analysis of MD trajectories revealed that -doxepin adopts a more restricted conformation upon binding, consistent with its enthalpy-driven interaction and reduced conformational entropy. These findings indicate that HR distinguishes between - and -isomers not only by affinity but also through distinct thermodynamic fingerprints. This study provides mechanistic insight into the enthalpy-entropy trade-off in GPCR-ligand interactions, highlighting the importance of conformational restriction and flexibility in designing ligands with optimized thermodynamic and functional properties.
ACS Med Chem Lett
· 2026 Feb · PMID 41704351
·
Full text
Molecular docking and dynamics simulations identified sulfonamide lead compound (ZINC818285131) as an α-glucosidase inhibitor. Subsequent structural modification yielded a novel series of furan/thiophene-containing sulf...Molecular docking and dynamics simulations identified sulfonamide lead compound (ZINC818285131) as an α-glucosidase inhibitor. Subsequent structural modification yielded a novel series of furan/thiophene-containing sulfonamide derivatives (-). In vitro assays revealed potent α-glucosidase inhibition for compounds , , , and , with IC values ranging from 2.03 μM to 2.69 μM. Notably, and (IC = 2.03 ± 0.05 μM and 2.14 ± 0.01 μM, respectively) surpassed standard acarbose IC = 3.20 ± 0.22 μM. Molecular docking suggested enhanced activity for and stems from hydrogen bonding and hydrophobic interactions with the enzyme. All compounds complied with Lipinski's rule of five. Comprehensive ADMET profiling indicated favorable properties for the most potent derivative, , which also exhibited promising antioxidant and anticancer potential. These findings may advance the discovery of new therapies for type-2 diabetes and bladder cancer.
ACS Med Chem Lett
· 2026 Feb · PMID 41704350
·
Full text
This patent describes novel substituted benzisoxazole sulfonamides as lysine acetyl transferase (KAT) inhibitors with potential applications in cancer therapy. It provides details on the synthesis of novel substituted be...This patent describes novel substituted benzisoxazole sulfonamides as lysine acetyl transferase (KAT) inhibitors with potential applications in cancer therapy. It provides details on the synthesis of novel substituted benzisoxazole sulfonamides, their pharmaceutical composition, and the use in the treatment of cancers.
ACS Med Chem Lett
· 2026 Feb · PMID 41704349
·
Full text
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 f...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.
ACS Med Chem Lett
· 2026 Feb · PMID 41704348
·
Full text
Recent psychedelic patent activity highlights a strategic shift from experiential framing toward chemically and pharmacokinetically precise neurotherapeutics. Four recent patent applications collectively span solid-state...Recent psychedelic patent activity highlights a strategic shift from experiential framing toward chemically and pharmacokinetically precise neurotherapeutics. Four recent patent applications collectively span solid-state control of psilocybin, exposure-shaped intramuscular and infusion-based dosing, and chemically diversified monoaminergic scaffolds with defined transporter and receptor pharmacology. Together, these disclosures outline a platform-level evolution toward reproducible, mechanism-informed psychedelic medicines.
ACS Med Chem Lett
· 2026 Feb · PMID 41704347
·
Full text
Provided herein are novel compounds as GIPR agonists, pharmaceutical compositions, use of such compounds in treating type 2 diabetes mellitus and obesity, and processes for preparing such compounds.Provided herein are novel compounds as GIPR agonists, pharmaceutical compositions, use of such compounds in treating type 2 diabetes mellitus and obesity, and processes for preparing such compounds.
Mahmood SU, Boddu RK, Eberhard J
… +8 more, Hoffman CS, Gordon J, Colussi D, Childers W, Amurrio E, Danaher M, Kelly MP, Rotella DP
ACS Med Chem Lett
· 2026 Feb · PMID 41704346
·
Full text
Previous work demonstrated target engagement with an orally bioavailable, potent, selective PDE11A4 inhibitor in the mouse hypothalamus. This compound was limited by low aqueous solubility, stimulating the need for alter...Previous work demonstrated target engagement with an orally bioavailable, potent, selective PDE11A4 inhibitor in the mouse hypothalamus. This compound was limited by low aqueous solubility, stimulating the need for alternative leads with improved pharmaceutical properties to carry out efficacy studies. This paper outlines optimization of a pyrrolopyrimidine hit leading to a potent, selective PDE11A4 inhibitor with improved pharmaceutical properties and promising activity in cell-based models of enzyme activity.
Simon KT, Hailemariam SE, Friedman E
… +4 more, Wen YW, Freaney M, Barker-Haliski M, Isoherranen N
ACS Med Chem Lett
· 2026 Feb · PMID 41696650
·
Full text
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 consumpti...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 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.
Damghani T, Song S, Lin KS
… +2 more, Li J, Heppner DE
ACS Med Chem Lett
· 2026 Jan · PMID 41684669
·
Full text
Inhibitors targeting mutant EGFR remain a persistent need in combating drug resistance in non-small cell lung cancer. To better understand the molecular factors involved in targeting T790M and C797S mutations, we determi...Inhibitors targeting mutant EGFR remain a persistent need in combating drug resistance in non-small cell lung cancer. To better understand the molecular factors involved in targeting T790M and C797S mutations, we determined X-ray cocrystal structures of fourth-generation inhibitors BI-8128 and BI-4732. Analysis from molecular dynamics and thermodynamic integration calculations correlated with biochemical and cellular measurements indicate that BI-8128 binds the double T790M/C797S more strongly than the single mutations individually. This observation showcases strengths in the design of these fourth-generation EGFR inhibitors as profile criteria require drugs to inhibit an array of oncogenic and drug resistance mutations.
Nayeen MJ, Thomas AG, Kundu B
… +8 more, Carlyle E, Hin N, Hin P, Pal A, Paule J, Rais R, Slusher BS, Tsukamoto T
ACS Med Chem Lett
· 2026 Feb · PMID 41675922
·
Full text
Canavan disease (CD) is an autosomal recessive genetic disorder caused by mutations in the ASPA gene, which encodes the enzyme aspartoacylase. These mutations lead to a deficient enzymatic activity and increased concentr...Canavan disease (CD) is an autosomal recessive genetic disorder caused by mutations in the ASPA gene, which encodes the enzyme aspartoacylase. These mutations lead to a deficient enzymatic activity and increased concentrations of its substrate, -acetylaspartate (NAA), in the brain and other tissues. Aspartate -acetyltransferase, encoded by the N-acetyltransferase 8-like (NAT8L) gene, catalyzes the biosynthesis of NAA from aspartate and acetyl-CoA. Therefore, inhibition of NAT8L has been implicated as a promising therapeutic strategy for CD by normalizing NAA levels in the brain. Our high throughput screening campaign followed by a rigorous hit validation process identified 2-(2-fluorophenoxy)-1-(3-((3-(thiophen-3-yl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-1-yl)ethan-1-one () as a low micromolar, noncarboxylic acid inhibitor of NAT8L. Subsequent structural optimization led to the discovery of two submicromolar NAT8L inhibitors. Although these inhibitors displayed high clearance in liver microsomes, the new scaffold, devoid of a carboxylic acid moiety, could potentially lead to potent and brain-penetrant NAT8L inhibitors through further molecular refinement.
Rosas-Lemus M, Athe S, Minasov G
… +16 more, Pattie JA, Brunzelle JS, Chau I, Li F, Vedadi M, Ma H, Ramanathan A, Becker ME, Hope TJ, Abdelkarim H, Grudzien P, Gaponenko V, Montgomery JE, Moellering RE, Rawal VH, Satchell KJF
ACS Med Chem Lett
· 2026 Feb · PMID 41568342
·
Full text
To address the ongoing threat of SARS-CoV-2 and potential emergence of novel coronaviruses, we employed a comprehensive strategy to identify and synthesize inhibitors of coronavirus methyltransferases with chemical analo...To address the ongoing threat of SARS-CoV-2 and potential emergence of novel coronaviruses, we employed a comprehensive strategy to identify and synthesize inhibitors of coronavirus methyltransferases with chemical analogs of -adenosylhomocysteine (SAH). Two analogs, designated and , inhibit both mouse hepatitis virus and SARS-CoV-2 replication. Compound was the most potent with half-maximal inhibition of biochemical activity at 0.2 μM and antiviral activity at ∼20 μM. This compound also has low cytotoxicity and preferentially inhibits nsp14 over nsp16 and human methyltransferases. Furthermore, molecular docking based on a newly determined crystal structure of the apo nsp16-nsp10 complex predicts that occupies both the -adenosylmethione and Gppp binding pockets of nsp14 and nsp16. Selectivity of for nsp14 is likely due to the enhanced structural stability of the nsp14 binding pocket relative to nsp16. These findings highlight SAH analogs as scaffolds for pan-coronavirus therapeutics and underscore the value of structure-guided design in antiviral drug discovery.
ACS Med Chem Lett
· 2026 Jan · PMID 41531986
·
Full text
Membrane-associated carbonic anhydrase (CA IX) is overexpressed in multiple cancers, making it a compelling target for therapeutics, yet measuring small molecule binding is challenging outside its native environment. Sur...Membrane-associated carbonic anhydrase (CA IX) is overexpressed in multiple cancers, making it a compelling target for therapeutics, yet measuring small molecule binding is challenging outside its native environment. Surface Plasmon Resonance Microscopy (SPRM) enables label-free kinetic measurements on whole cells, revealing critical insights that are often missed by conventional assays that require receptor purification. Here, we pioneer the use of SPRM to study kinetic interactions of five sulfonamide-based small molecule inhibitors (Acetazolamide, Sulfanilamide Furosemide, Dansylamide, and 4-Carboxybenzenesulfonamide-(4-CBS)) with CA IX on live Ramos B suspension cells. SPRM measurements were in close agreement with the literature and demonstrated a low coefficient of variation (% CV) of 6.8%. Additionally, Sulfanilamide demonstrated a 16-fold stronger affinity in its native membrane-bound state than in its purified state. This pioneering study establishes SPRM for label-free kinetic measurements of small molecule interactions on live suspension cells .
ACS Med Chem Lett
· 2026 Jan · PMID 41531985
·
Full text
Emerging psychedelic therapeutics increasingly rely on mechanistic precision, receptor selectivity, and pharmacokinetic control. Recent inventions introduce simplified iboga analogs with tunable polypharmacology, real-ti...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.
Han B, Wang H, Wu X
… +5 more, Yang L, Shen A, Yang X, Wang X, Zhang Q
ACS Med Chem Lett
· 2026 Jan · PMID 41531984
·
Full text
Inhibition of histone deacetylase 6 (HDAC6) has become a promising therapeutic strategy for central nervous system diseases. To address the metabolic instability of our previously discovered brain-penetrant HDAC6 inhibit...Inhibition of histone deacetylase 6 (HDAC6) has become a promising therapeutic strategy for central nervous system diseases. To address the metabolic instability of our previously discovered brain-penetrant HDAC6 inhibitor , herein the identification of metabolic sites and structural optimization based on were carried out. The most potent compound, , potently and selectively inhibited HDAC6 (IC = 4.0 nM; >176-fold selectivity) and exhibited a 2-fold longer half-life in rat liver microsomes ( = 29.49 min) than . It stabilized the HDAC6 complex in silico and increased the level of acetylated α-tubulin in SH-SY5Y cells. , significantly reduced cerebral infarction (from 32.87% to 13.13%) in the rat MCAO model. These results demonstrate that is a metabolically stable, highly selective HDAC6 inhibitor with compelling neuroprotective efficacy, warranting its further development for ischemic stroke.
ACS Med Chem Lett
· 2026 Jan · PMID 41531983
·
Full text
Recent advances in targeted protein degradation combine dual E3 ligase-recruiting multivalent PROTACs, Survivin as a predictive biomarker for therapeutic responsiveness, and dendrimer-PROTAC conjugates for CNS and inflam...Recent advances in targeted protein degradation combine dual E3 ligase-recruiting multivalent PROTACs, Survivin as a predictive biomarker for therapeutic responsiveness, and dendrimer-PROTAC conjugates for CNS and inflammation-targeted delivery. Together, these innovations form a synergistic framework for potent, selective, and biomarker-guided degraders with enhanced delivery, offering a promising blueprint for next-generation therapeutics in oncology and beyond.
Griadunova AA, Petrone NL, Maker MS
… +7 more, Pallares B, Leung T, Shim AN, Yilmaz ÖH, Goldberg JM, Braverman J, Wang F
ACS Med Chem Lett
· 2026 Jan · PMID 41531982
·
Full text
Efflux pump-mediated multidrug resistance is a common mechanism by which cancer cells reduce the efficacy of a broad range of small-molecule therapeutics. We discovered that substituting the 4'-hydroxy group of doxorubic...Efflux pump-mediated multidrug resistance is a common mechanism by which cancer cells reduce the efficacy of a broad range of small-molecule therapeutics. We discovered that substituting the 4'-hydroxy group of doxorubicina known efflux pump substratewith an -amino group results in a new compound, doxorubamine, which exhibits substantially improved activity against drug-sensitive and -resistant cancer cells and organoids. Mechanistic studies reveal that doxorubamine is a poor substrate of P-glycoprotein, and it thus retains high potency against multidrug-resistant cancer. This synthetic modification provides a promising strategy for circumventing multidrug resistance beyond conventional approaches that rely on efflux pump inhibition.
Barasa L, DeOrsey L, O'Reilly MD
… +12 more, Choudhary S, Cahill SE, Mathur A, Allabaji A, Vidadala SR, Sarkar SK, Patil SN, Kalonia H, Hale J, Humphries F, Fitzgerald KA, Thompson PR
ACS Med Chem Lett
· 2026 Jan · PMID 41531981
·
Full text
The cGAS-STING pathway is a critical component of the innate immune system, responsible for detecting cytosolic DNA and triggering inflammatory signaling. While essential for host defense, aberrant activation of this pat...The cGAS-STING pathway is a critical component of the innate immune system, responsible for detecting cytosolic DNA and triggering inflammatory signaling. While essential for host defense, aberrant activation of this pathway is linked to a range of inflammatory and autoimmune disorders. Consequently, STING has emerged as a compelling therapeutic target. Herein we report the development of the first reversible covalent STING inhibitor, i.e., which employs an alkyne-thiazole warhead. inhibits STING-dependent signaling in both mouse and human systems. Notably, maintains activity against the most prevalent human STING variant (R232), effectively suppresses STING signaling in primary human CD14+ monocytes, and exhibits moderate metabolic stability. Collectively, these findings highlight as a promising scaffold for the development of therapeutics targeting STING-driven inflammatory and autoimmune diseases.
Wu J, Liu Y, Li D
… +12 more, Wang L, Neidhart W, Chen B, Hochstrasser R, Kuglstatter A, Gasser R, Qiu H, Shi T, Chao SK, Gao J, Shen HC, Tan X
ACS Med Chem Lett
· 2026 Jan · PMID 41531980
·
Full text
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 al...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 , 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 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.
ACS Med Chem Lett
· 2026 Jan · PMID 41531979
·
Full text
Recent innovations showcase the power of selectivity in precision medicine. Brain-penetrant TYK2 inhibitors target autoimmune and neuroinflammatory disease, fetal cell diagnostics improve prenatal screening, and biomarke...Recent innovations showcase the power of selectivity in precision medicine. Brain-penetrant TYK2 inhibitors target autoimmune and neuroinflammatory disease, fetal cell diagnostics improve prenatal screening, and biomarker signatures refine checkpoint immunotherapy. Together, these advances highlight how molecular, cellular, and patient-level selectivity drives therapeutic precision across neurology, oncology, immunology, and reproductive health, reshaping diagnostics and treatment strategies from early development through complex disease.
ACS Med Chem Lett
· 2026 Jan · PMID 41531978
·
Full text
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.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.