Zhao X, Zhao Y, Fang Z
… +4 more, Wei N, Chen J, Wang Q, Yan X
ACS Med Chem Lett
· 2026 May · PMID 42157842
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Targeted covalent inhibitors (TCIs), a class of pharmaceuticals that specifically recognize disease-related proteins and form covalent bonds for precise therapy, still suffer from side effects and diminished efficacy due...Targeted covalent inhibitors (TCIs), a class of pharmaceuticals that specifically recognize disease-related proteins and form covalent bonds for precise therapy, still suffer from side effects and diminished efficacy due to poor tumor cell specificity. To address this, we present a new cell/protein "Double Insurance" targeting strategy through constructing a novel antibody-TCI conjugate (Ab-TCI), which comprises a monoclonal antibody (Loncastuximab), a TCI (As-Ibt) for Bruton's tyrosine kinase (BTK), and between them an arsenic-thiol bond as a new cleavable linker. This Ab-TCI enables B-cell lymphoma cell recognition, internalization, and release of As-Ibt by intracellular GSH, efficiently inhibiting BTK, and effectively suppressing the growth of xenograft tumors. To our knowledge, this is the first Ab-TCI enabling simultaneous dual targeting capabilities for cancer cells and kinase, achieving a remarkable improvement in drug efficacy. New potent dual-targeting Ab-TCIs could be inspired by integrating different FDA approved TCIs and antibodies through our strategy for cancer treatment.
Brill ZG, Christian AH, Rico L
… +29 more, Schneider SE, Phillips EM, Winston MS, Krishnamurthy H, Hennessy ET, Mansoor UF, Xiao D, Su J, Liu P, Plummer C, Palmieri A, Vela Ramirez J, Hill A, Dewey W, Tatosian D, Rindgen D, Ogunbodede O, Smotrov N, Piesvaux J, Ciaccio P, Fan P, Afshar R, Daublain P, Presland J, Otte KM, Ali A, Cumming J, Ranganath S, DeMong D
ACS Med Chem Lett
· 2026 May · PMID 42157841
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The tumor microenvironment is characterized by conditions that frequently lead to immunosuppression, allowing tumors to escape immune surveillance and potentially contributing to resistance to immuno-oncology therapeutic...The tumor microenvironment is characterized by conditions that frequently lead to immunosuppression, allowing tumors to escape immune surveillance and potentially contributing to resistance to immuno-oncology therapeutics. A potential strategy for combination therapy with checkpoint inhibitors is to target the A and A receptors with a dual antagonist that could rescue T cells from adenosine-mediated suppression. Herein, we describe efforts toward highly potent and selective A/A dual receptor antagonists with improved pharmacokinetic and solubility profiles compared to initial lead compounds. We discovered that a 1,3-cyclobutane linker between our triazoloquinazoline core and a pendant aryl substituent decorated with a tertiary carbinamine provided a desirable balance of potency and physicochemical properties. Our lead molecule demonstrated an exceptional effective half-life across multiple species. Chemistry advances guided by high-throughput experimentation (HTE) facilitated efficient, late-stage access to complex derivatives in this series.
ACS Med Chem Lett
· 2026 May · PMID 42157839
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This patent discloses tetrahydropyrrolooxazolones as novel receptor-interacting protein kinase 1 (RIPK1) inhibitors as potential treatments for RIPK1-related diseases. It provides details in the synthesis of the tetrahyd...This patent discloses tetrahydropyrrolooxazolones as novel receptor-interacting protein kinase 1 (RIPK1) inhibitors as potential treatments for RIPK1-related diseases. It provides details in the synthesis of the tetrahydropyrrolooxazolones, pharmaceutical compositions, and therapeutic applications for RIPK1-related diseases.
Tarby CM, Hart A, Wan H
… +32 more, He L, Tokarski J, Fink B, Zhao Y, Huynh T, Gavai A, Zimmermann K, Vite G, Vyas D, Inghrim J, Obermeier M, Fura A, Elzinga P, Hunt J, Roongta U, Henley B, Lippy J, Mathur A, Wu DR, Li P, Raghavan N, Everlof G, Rupnow B, Lee F, Fargnoli J, Tredup J, Kiefer SE, Calambur D, Gupta A, Vetrichelvan M, Subbaiah MAM, Purandare AV
ACS Med Chem Lett
· 2026 May · PMID 42157838
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Casein kinase 2 (CK2), comprising the catalytic subunits CK2α and CK2α', is a highly conserved and constitutively active serine/threonine kinase that is implicated in oncogenic signaling and tumor maintenance, making it...Casein kinase 2 (CK2), comprising the catalytic subunits CK2α and CK2α', is a highly conserved and constitutively active serine/threonine kinase that is implicated in oncogenic signaling and tumor maintenance, making it an attractive therapeutic target. We report a medicinal chemistry campaign that delivered an imidazotriazine pan-CK2 series culminating in BMS-135 and its phosphate prodrug BMS-159. Structure-guided design enabled a scaffold hop from imidazopyridazine to imidazotriazine that improved kinome selectivity while preserving critical hinge and Lys68 interactions. Iterative SAR optimization mitigated hERG liability by modulating distal basicity and enhanced metabolic stability via a C8 -ethyl substitution that blocked N-dealkylation, delivering BMS-135 as a sub-nanomolar CK2 inhibitor with favorable ADMET properties and robust antitumor efficacy across xenograft and patient-derived xenograft models. Subsequent pharmaceutical optimization through a prodrug strategy afforded BMS-159, which markedly improved solubility and enabled oral delivery of the parent with acceptable bioavailability and pharmacokinetic properties suitable for further development.
ACS Med Chem Lett
· 2026 May · PMID 42157837
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Provided herein are novel pyrrolopyridazine compounds as VEGFR inhibitors, pharmaceutical compositions, use of such compounds in treating cancer and processes for preparing such compounds.Provided herein are novel pyrrolopyridazine compounds as VEGFR inhibitors, pharmaceutical compositions, use of such compounds in treating cancer and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 May · PMID 42157836
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Photo-immunotherapy combines phototherapy and immunotherapy, which can eliminate primary tumors and induce host immunity to control distant metastases. However, the effectiveness may be attenuated by the tumor defense me...Photo-immunotherapy combines phototherapy and immunotherapy, which can eliminate primary tumors and induce host immunity to control distant metastases. However, the effectiveness may be attenuated by the tumor defense mechanisms associated with glutamine metabolism regulation. In this work, a self-assembled stimulator was prepared for glutamine-starvation-potentiated photo-immunotherapy, which is composed of telaglenastat as the glutaminase inhibitor, chlorin e6 (Ce6) as the photosensitizer, and interferon stimulatory DNA (ISD). Ce6 transfers energy from light to molecular oxygen, generating reactive oxygen species (ROS). Telaglenastat assists in the downregulation of endogenous glutathione. Thus, ROS neutralization can be prevented, and the photodynamic therapy effect is enhanced. Additionally, the cGAS-STING signaling pathway activated by ISD remodels the tumor microenvironment by polarizing M2-type tumor-associated macrophages into M1, which finally enhances immunogenic cell death. The prepared nanomedicine combines glutamine starvation and a photo-immunotherapy strategy, offering new insights into cancer treatment.
Ipatova DA, Ikonnikova VA, Kungurtsev KD
… +9 more, Kashapov AI, Shafikov RR, Kartsev VG, Glushkov AK, Myasnyanko IN, Baranov MS, Mikhaylov AA, Dontsova OA, Skvortsov DA
ACS Med Chem Lett
· 2026 May · PMID 42157835
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The design of novel small molecules with high selectivity for anticancer action remains a priority in the development of chemotherapy. A combination of the "privileged scaffold" of the chroman-4-one with rigid spirocycli...The design of novel small molecules with high selectivity for anticancer action remains a priority in the development of chemotherapy. A combination of the "privileged scaffold" of the chroman-4-one with rigid spirocyclic structures offers a strategy for modulating the specificity of action. A collection of 28 spirocyclohexane-chroman-4-one derivatives was screened using fluorescence cell coculture test, and compound was selective in the breast cancer model. Structure-activity relationship analysis was performed within three rounds of optimization with rational synthesis of derivatives. Reduction of the carbonyl group to hydroxyl and incorporation of a dioxolane group into the spirocyclohexane ring reduced toxicity toward noncancerous VA13 and MCF10A cells. The lead compound with this elaborated structure exhibited cytotoxicity against MCF7 cells (IC ≈ 3.8 μM) and remained significantly less cytotoxic to both noncancerous cells. It highlights the potential of spirocyclic-fused chroman-4-ones as selective cytotoxic agents through rigidifying the molecular scaffold and precisely tuning the functional group positioning.
Tran K, Lavoie H, Wahhab A
… +15 more, Garrido D, Jo CH, Poupart MA, Arya T, Beautrait A, Killoran R, Dicaire-Leduc C, Bonneil É, Osborne M, Schuetz DA, Shaikh F, Thibault P, Smith MJ, Marinier A, Therrien M
ACS Med Chem Lett
· 2026 May · PMID 42157834
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Despite therapeutic advances against RAS mutations in cancer, acquired resistance frequently arises. Several secondary mutations at the binding sites effectively confer resistance to both Switch-II inhibitors and cycloph...Despite therapeutic advances against RAS mutations in cancer, acquired resistance frequently arises. Several secondary mutations at the binding sites effectively confer resistance to both Switch-II inhibitors and cyclophilin-A molecular glues. This underscores the need for RAS inhibitors that engage alternative binding pockets or operate through novel mechanisms. Here, we report the design of 10-mer macrocyclic peptides that mimic the FG-loop of the NS1 monobody, which targets the allosteric α4-α5-β6 surface of H/KRAS to disrupt RAS clustering and downstream signaling. These noncovalent inhibitors bind to H/KRAS with equivalent potencies, regardless of nucleotide state or the presence of oncogenic mutations (G12D, G12V, G13R, Q61K), and their binding site was confirmed by NMR and X-ray crystallography. Furthermore, covalent analogs targeting Cys118 were shown to label RAS and in complete cell lysates. Finally, we demonstrated that the key pharmacophores are connectable, providing a foundation for the development of smaller allosteric H/KRAS inhibitors.
Romanowska J, Wawrzyniak D, Szymanska-Michalak A
… +6 more, Framski G, Pawlowicz-Perczak A, Sobkowski M, Stawinski J, Rolle K, Kraszewski A
ACS Med Chem Lett
· 2026 May · PMID 42157833
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Three series of 5-fluoro-2'-deoxyuridine (FdU) nucleotide analogues were studied as potential antiglioma pronucleotides. The 5'-OH position was esterified with H-phosphonate, phosphate, and acylphosphate residues, all of...Three series of 5-fluoro-2'-deoxyuridine (FdU) nucleotide analogues were studied as potential antiglioma pronucleotides. The 5'-OH position was esterified with H-phosphonate, phosphate, and acylphosphate residues, all of which had negative charges. Additionally, some carried protecting groups of varying lipophilicity at the 3'-OH position. The acylphosphate moiety also contained different hydrocarbon substituents. The amphiphilic nature of these compounds should render them water-soluble and facilitate their permeation through the cell membranes. Inside the cell, they were expected to be converted to 5-fluoro-2'-deoxyuridine 5'-phosphate, a highly effective inhibitor of thymidylate synthetase. Two of the studied new FdU derivatives exhibited promising antiproliferative activity against the glioblastoma multiforme T98G cell line, an order of magnitude better than that of the parent nucleoside.
ACS Med Chem Lett
· 2026 May · PMID 42157832
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KRAS remains a central yet formidable oncogenic driver across multiple cancer types. Patent application WO 2026/039365 A1 discloses a structurally diverse class of small molecules designed to modulate KRAS activity acros...KRAS remains a central yet formidable oncogenic driver across multiple cancer types. Patent application WO 2026/039365 A1 discloses a structurally diverse class of small molecules designed to modulate KRAS activity across both mutant and wild-type forms. By expanding chemical flexibility and introducing versatile binding modes, this invention supports therapeutic intervention in RAS-driven malignancies. The disclosed compounds represent a meaningful advance toward deeper pathway suppression and broader clinical applicability.
Sahin Z, Rivera M, Yang Y
… +5 more, Liu K, Sahin GPC, Bacsa J, Pelly SC, Liotta DC
ACS Med Chem Lett
· 2026 May · PMID 42157831
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In continuation of our previous work wherein we described novel, nonpeptidic competitive inhibitors of the SARS-CoV-2 main protease, we here describe our efforts to improve upon these compounds by improving water solubil...In continuation of our previous work wherein we described novel, nonpeptidic competitive inhibitors of the SARS-CoV-2 main protease, we here describe our efforts to improve upon these compounds by improving water solubility and metabolic stability. As predicted by FEP+ solubility studies, disrupting the coplanar arrangement of the aromatic rings led to significantly improved compound aqueous solubility, unfortunately with an unacceptable loss in potency. Attempts to improve compound metabolic stability by avoiding aromatic moieties occupying the S4 pocket, while retaining compound potency by modification of the pyridyl ring occupying the S1 pocket, were also investigated.
ACS Med Chem Lett
· 2026 May · PMID 42157830
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Provided herein are novel indoline derivatives serotonergic psychedelic agents as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating psychosis, mental illness and central nervous system (CNS)...Provided herein are novel indoline derivatives serotonergic psychedelic agents as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating psychosis, mental illness and central nervous system (CNS) disorders and processes for preparing such compounds.
Bonardi A, Ferraroni M, Gratteri P
… +2 more, Supuran CT, Angeli A
ACS Med Chem Lett
· 2026 May · PMID 42157829
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AT-121 is a bifunctional ligand acting as a partial agonist at both μ-opioid and nociceptin receptors, designed to retain potent analgesia while reducing opioid-associated side effects. Carbonic anhydrases (CAs) catalyze...AT-121 is a bifunctional ligand acting as a partial agonist at both μ-opioid and nociceptin receptors, designed to retain potent analgesia while reducing opioid-associated side effects. Carbonic anhydrases (CAs) catalyze the reversible conversion of carbon dioxide to bicarbonate and protons and, in the central nervous system, play key roles in neuronal excitability, synaptic transmission, and pain processing. Inhibition profiling across all human CA isoforms demonstrated activity against several cytosolic enzymes, as well as membrane-associated isoforms hCA IV and XII, the latter showing the highest inhibitory potency (K = 70.1 nM). X-ray crystallography of the hCA II-AT-121 complex highlighting dual binding conformations mediated by an aliphatic sulfamide moiety within the enzyme active site. Complementary docking simulations across additional isoforms supported these observations. Collectively, these findings suggest that AT-121 operates a multimodal mechanism combining dual opioid receptor activation with CA inhibition, supporting its potential as a safer, nonaddictive analgesic strategy.
Apprato G, Bertola M, Locatelli A
… +3 more, Caron G, Mauri A, Ermondi G
ACS Med Chem Lett
· 2026 May · PMID 42157828
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Proteolysis-targeting chimeras (PROTACs) represent a promising modality for targeted protein degradation, yet their structural complexity complicates systematic design and analysis. Bellerophon is a new computational too...Proteolysis-targeting chimeras (PROTACs) represent a promising modality for targeted protein degradation, yet their structural complexity complicates systematic design and analysis. Bellerophon is a new computational tool that automatically decomposes PROTACs into their warhead, linker, and E3 ligase ligand directly from molecular structure. By enabling automated and standardized decomposition of degraders, the tool facilitates drug design at different levels: Bellerophon demonstrated versatility for moiety replacement (ARV-110), large-scale annotation (PROTAC-DB) and linker analysis (IRAK4 data set). The tool is freely available through a user-friendly web interface, with open-source code to encourage transparency and collaborative development in chemical biology and medicinal chemistry.
Dialer C, Krüger S, Wagener M
… +21 more, Mülbaier M, Peil S, Marigo M, Hagendorf S, Cao L, Molina CR, Morgan P, Young C, Ribeiro LR, Slynko I, Ritter S, Guberman M, Hass M, Klosky S, la Tendresse U, Gussmann C, Kühnert S, Peters S, Reichardt-Ockenfeld S, Depmeier H, Jakob F
ACS Med Chem Lett
· 2026 May · PMID 42157827
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Inhibitors of voltage-gated sodium channel 1.8 (Na1.8) are anticipated to provide opioid-free treatment for acute pain and potentially chronic neuropathic pain. Herein, we report on the discovery of a novel series of Na1...Inhibitors of voltage-gated sodium channel 1.8 (Na1.8) are anticipated to provide opioid-free treatment for acute pain and potentially chronic neuropathic pain. Herein, we report on the discovery of a novel series of Na1.8 inhibitors characterized by high selectivity over other sodium channels. Utilizing a pharmacophore model trained on literature data, we identified the initial hit compound through virtual screening. During the hit-to-lead optimization phase, we improved the potency and clearance of the lead compounds. Structural modifications and control of lipophilicity and other physicochemical parameters resulted in a favorable safety and drug-drug interaction profile for compound . Key to optimizing the clearance was the identification of a metabolic hotspot via metabolite identification (MetID) experiments. The lead compound exhibited a long half-life and high exposure ( ) in the pain-relevant target tissue (DRG) in rat PK studies. These findings highlight potential of these compounds for further optimization as nonopioid therapeutics.
A Thirumurthy M, Aguilar Díaz de León JS, Pan S
… +1 more, Ly N
ACS Med Chem Lett
· 2026 May · PMID 42157826
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The glucagon peptide 1 receptor (GLP-1R), a class-B-type G protein-coupled receptor (GPCR), is a key therapeutic target for many metabolic disorders, including obesity and type 2 diabetes, due to its central role in gluc...The glucagon peptide 1 receptor (GLP-1R), a class-B-type G protein-coupled receptor (GPCR), is a key therapeutic target for many metabolic disorders, including obesity and type 2 diabetes, due to its central role in glucose homeostasis and insulin secretion. Despite its pharmacological importance, studying the binding kinetics of its multidomain engagement with peptide ligands remains a challenge using purified receptor systems. The isolated forms fail to capture the dynamic behavior of membrane-bound GPCRs in a physiologically relevant context. A deeper understanding of the interaction kinetics of agonist and antagonist binding to GLP-1R domains is essential for rational drug design, as the activation of the receptor depends on distinct binding modes that modulate downstream signaling efficacy. Here we employ surface plasmon resonance microscopy (SPRM) on HEK293T cells overexpressing GLP-1R to visualize and quantify the label-free kinetic interactions of ligands on whole single cells in real time. Using three different agonists (GLP-1, liraglutide, exendin-4) and one antagonist (exendin-9), we demonstrate that the agonists exhibit a two-mode/bivalent binding behavior with C-terminal engagement of the extracellular domain (ECD) and N-terminal engagement of the transmembrane domain (TMD). In contrast, the antagonist exendin-9 binds with a single mode, exclusively to the ECD. Importantly, SPRM resolves not only the presence of dual-domain engagement but also the stability and heterogeneity of these interactions, enabling discrimination between full and partial agonism. Notably, liraglutide displays the highest interaction affinity and the greatest amount of activation through TMD binding, which agrees with its known structural optimization and superior therapeutic performance. This study highlights SPRM as a powerful, label-free platform for probing the on-cell binding kinetics of GPCR interactions with peptides, providing quantitative insights into the activation efficiency of agonists and selectivity of antagonists in ways conventional receptor assays cannot.
ACS Med Chem Lett
· 2026 May · PMID 42157825
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This patent demonstrates a series of macrocycle-based compounds that antagonize stimulator of interferon genes (STING), a key role in the innate immune response implicated in autoimmune diseases. These compounds, along w...This patent demonstrates a series of macrocycle-based compounds that antagonize stimulator of interferon genes (STING), a key role in the innate immune response implicated in autoimmune diseases. These compounds, along with their pharmaceutically acceptable salt thereof, are intended for the treatment of autoimmune related diseases driven by STING-mediated pathways.
ACS Med Chem Lett
· 2026 May · PMID 42157824
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Estrogen receptor alpha (ERα) is the defining therapeutic target in hormone receptor-positive breast cancer, yet acquired resistance remains a persistent barrier to durable clinical benefit. Patent application WO 2026/03...Estrogen receptor alpha (ERα) is the defining therapeutic target in hormone receptor-positive breast cancer, yet acquired resistance remains a persistent barrier to durable clinical benefit. Patent application WO 2026/039467 A1 discloses small molecules that activate an anticipatory unfolded protein response (a-UPR) through ERα, converting receptor engagement into selective cytotoxic stress. This mechanism diverges fundamentally from classical antagonism or degradation and demonstrates preferential activity in ERα-positive tumor modelsoffering a conceptually distinct strategy for overcoming endocrine resistance.