ACS Med Chem Lett
· 2026 Mar · PMID 41847648
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Recent innovations in oncology drug discovery reveal a convergent strategy built on biological dependency, protein fate control, and quantitative network analysis. Epigenetic protein degradation enables durable transcrip...Recent innovations in oncology drug discovery reveal a convergent strategy built on biological dependency, protein fate control, and quantitative network analysis. Epigenetic protein degradation enables durable transcriptional rewiring, helicase inhibition exploits synthetic-lethal DNA repair vulnerabilities, and DNA-barcoded interactomics quantifies higher-order protein complexes. Together, these advances redefine precision oncology as a system-level discipline driven by context, modality, and measurable biological consequence.
ACS Med Chem Lett
· 2026 Mar · PMID 41847647
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α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are tetrameric ionotropic glutamate receptors that mediate fast excitatory synaptic transmission in the brain and represent important therapeutic targ...α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are tetrameric ionotropic glutamate receptors that mediate fast excitatory synaptic transmission in the brain and represent important therapeutic targets for neurological disorders. Positive allosteric modulators (PAMs) of AMPA receptors enhance rapid excitatory signaling by increasing receptor's sensitivity to glutamate and have been widely explored as agents to improve cognitive function in central nervous system (CNS) diseases. Structural modification of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) analogs is a key strategy to develop potent AMPAR PAMs. A recent study reported a new pharmacomodulation strategy on the benzene ring of BTDs through systematic structure-activity relationship (SAR) optimization. This work led to the identification of compound (BPAM363), which exhibits improved pharmacological properties, robust cognitive-enhancing and neuroprotective effects. These findings provide valuable insight for further development of AMPAR PAMs as therapeutic candidates for cognitive disorders.
Rodríguez JE, Lagos-Cruz JA, Villalobos-Molina R
… +3 more, Cuevas-Hernández RI, Gallardo-Ortíz IA, Andrade-Jorge E
ACS Med Chem Lett
· 2026 Mar · PMID 41847646
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Hypertension, a major cardiovascular risk factor, is often treated with peptide-derived angiotensin-converting enzyme inhibitors (ACEi), which can have several side effects. This study examined a new alternative: isoindo...Hypertension, a major cardiovascular risk factor, is often treated with peptide-derived angiotensin-converting enzyme inhibitors (ACEi), which can have several side effects. This study examined a new alternative: isoindoline and isoindoline-1,3-dione derivatives as nonpeptide ACE inhibitors. The synthesis and testing of these compounds involved both molecular docking studies and optimized inhibitory kinetic assays, along with acute toxicity tests in mice. isoindoline-1,3-dione, D-05, demonstrated the strongest ACE inhibition (IC = 416.4 μM) and effectively bound to the enzyme's catalytic active site . Additionally, isoindoline-1,3-diones showed lower toxicity in mice (LD > 1600 mg/kg) compared to isoindolines (LD < 1000 mg/kg). This reduced toxicity is attributed to the presence of fewer reactive secondary metabolites. These promising results highlight the potential of isoindoline-1,3-diones as innovative nonpeptide ACE inhibitors and support further studies to verify their antihypertensive effects.
ACS Med Chem Lett
· 2026 Mar · PMID 41847644
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This patent highlight describes the synthesis and assessment of a series of new inverse agonists targeting G protein-coupled receptor 6 (GPR6) based on pyridopyrazine analogs. It details their chemical synthesis, charact...This patent highlight describes the synthesis and assessment of a series of new inverse agonists targeting G protein-coupled receptor 6 (GPR6) based on pyridopyrazine analogs. It details their chemical synthesis, characterization, and biological activity assays.
ACS Med Chem Lett
· 2026 Mar · PMID 41847643
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Provided herein are novel pyrrolopyridazine VEGFR tyrosine kinase inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.Provided herein are novel pyrrolopyridazine VEGFR tyrosine kinase inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.
De-la-Cruz-Martínez L, Equihua-González D, Torres-Chacón DL
… +7 more, Ortiz-Barragán E, Torres-Valencia JM, Martínez-Casares RM, Pérez-Villanueva J, González-Andrade M, Almanza-Pérez JC, Cortés-Benítez F
ACS Med Chem Lett
· 2026 Mar · PMID 41847642
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Protein Tyrosine Phosphatase 1B (PTP1B) is a crucial enzyme that significantly modulates insulin and leptin signaling, making it a highly promising target for the treatment of type 2 diabetes (T2D). We previously reporte...Protein Tyrosine Phosphatase 1B (PTP1B) is a crucial enzyme that significantly modulates insulin and leptin signaling, making it a highly promising target for the treatment of type 2 diabetes (T2D). We previously reported the synthesis and inhibitory activity of FC-114, an indole-fused glycyrrhetinic acid derivative that potently inhibits PTP1B. In this study, we synthesized four FC-114 conjugates with amino acids at the C30 position to enhance their inhibitory activity against PTP1B . The results indicated that incorporating glycine (compound ) and serine (compound ) substantially enhanced inhibitory activity against PTP1B, achieving up to 4-fold greater potency, with submicromolar IC values of 0.64 and 0.54 μM, respectively. Inhibitory assessments of the short form (PTP1B) and long form (PTP1B) of PTP1B, along with enzymatic kinetics studies, molecular docking, and molecular dynamics analyses, suggested a mechanism consistent with uncompetitive inhibition, potentially involving a binding to the disordered C-terminal domain. Furthermore, both FC-114 conjugates with glycine () and arginine () significantly enhanced the mRNA expression of the GLUT4 receptor in C2C12 myoblast cells. Additionally, these compounds reduced glucose levels during the insulin tolerance test in streptozotocin-induced diabetic mice.
ACS Med Chem Lett
· 2026 Mar · PMID 41847641
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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 he...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.
ACS Med Chem Lett
· 2026 Mar · PMID 41847640
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The advent of immune checkpoint blockade therapy, exemplified by inhibitors targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis, has revolutionized the landscape of clinical oncology. De...The advent of immune checkpoint blockade therapy, exemplified by inhibitors targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis, has revolutionized the landscape of clinical oncology. Despite its remarkable success, therapeutic benefits remain limited to a subset of patients, highlighting the urgent need for more accurate methods of patient stratification. Conventional techniques for assessing PD-L1 expression, such as immunohistochemistry, provide static and localized information but lack the ability to capture whole-body distribution or temporal dynamics. In contrast, positron emission tomography (PET) offers a noninvasive approach for visualizing PD-L1 expression and disease burden . However, clinical translation of PD-L1-specific radiotracers has been hampered by suboptimal tumor accumulation and unfavorable pharmacokinetics. To address this limitation, a recent study established a disulfide-directed multicyclic peptide (DDMP) platform capable of generating high-affinity peptide ligands specifically designed for PD-L1 imaging and potential therapeutic applications.
ACS Med Chem Lett
· 2026 Mar · PMID 41847639
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This patent provides novel macrocycle compounds that inhibit key mutants (G12D/G13D) of the KRAS oncogene, which is the most frequently mutated in human cancers. These compounds, along with their pharmaceutical compositi...This patent provides novel macrocycle compounds that inhibit key mutants (G12D/G13D) of the KRAS oncogene, which is the most frequently mutated in human cancers. These compounds, along with their pharmaceutical compositions and protein complexes, are intended for the treatment of cancers driven by these mutations.
Merchant RR, Chernyak N, Lopez JA
… +16 more, Sharp PP, Mandal M, He J, Hruza A, Rearden P, Tatosian DA, Esmay J, Yang S, Cheng AC, Ellsworth K, Ogawa A, Piou T, Fier P, Hicks J, Sinz C, Ogawa AK
ACS Med Chem Lett
· 2026 Mar · PMID 41847638
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Plasma kallikrein (pKal) is a trypsin-like serine protease involved in the kallikrein-kinin, renin-angiotensin, and complement pathways, making it an attractive target for diseases, such as hereditary angioedema, diabeti...Plasma kallikrein (pKal) is a trypsin-like serine protease involved in the kallikrein-kinin, renin-angiotensin, and complement pathways, making it an attractive target for diseases, such as hereditary angioedema, diabetic mellitus complications, and cerebrovascular disorders. As part of an internal program to develop orally bioavailable small-molecule pKal inhibitors, we report lead optimization efforts within the spirocarbamate scaffold, highlighting a structure-based drug design strategy to engineer hydrogen bond interactions with -benzyl aminopyrazoles. Additionally, mitigation of time-dependent inhibition (TDI) liability and optimization of the overall profile were achieved through a two-pronged strategy: (1) incorporating increased Fsp modifications via -alkylation and (2) leveraging torsional strain in -aryl analogs.
Zhang H, Wang K, Wu X
… +4 more, Zhou R, Li C, Cai X, Zhuang Y
ACS Med Chem Lett
· 2026 Mar · PMID 41847637
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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...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 IC values <500 nM; notably, CX-6258 (IC = 473.7 nM) exhibited potent antiproliferative activity in MIA PaCa-2 and Panc-1 cell lines with low micromolar potencies (IC = 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.
ACS Med Chem Lett
· 2026 Mar · PMID 41847636
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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...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.
ACS Med Chem Lett
· 2026 Mar · PMID 41847635
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Ubiquitin-specific protease 1 (USP1) is a member of the deubiquitinating enzyme family that modulates the stability and biological activity of target proteins through the removal of ubiquitin modifications, thereby contr...Ubiquitin-specific protease 1 (USP1) is a member of the deubiquitinating enzyme family that modulates the stability and biological activity of target proteins through the removal of ubiquitin modifications, thereby contributing to tumor development and resistance to anticancer therapies. This patent summary focuses on the design and optimization of a class of small-molecule inhibitors that exhibit high potency and selectivity toward USP1.
Mandler MD, Zhu Y, Hollenbeck EC
… +20 more, Ziegler M, Posy SL, Mukundan S, Halpern OS, Driscoll JP, Wang T, Huang L, Fernando G, Jung H, Li L, Cutrone J, Baswar D, Eapen P, Traeger SC, Srivastava S, Olsen J, Everlof GG, Trujillo G, Ellsworth BA, Regueiro-Ren A
ACS Med Chem Lett
· 2026 Mar · PMID 41847634
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A screen for small-molecule antagonists of Toll-like receptor 9 (TLR9) uncovered a triazine chemotype hit with potential liabilities, including a nitroarene, a hydrazone, and a free phenol. Systematic replacement of thes...A screen for small-molecule antagonists of Toll-like receptor 9 (TLR9) uncovered a triazine chemotype hit with potential liabilities, including a nitroarene, a hydrazone, and a free phenol. Systematic replacement of these liabilities led to the identification of compound , which maintained submicromolar TLR9 antagonism while exhibiting oral bioavailability and robust pharmacodynamic effects in a bleomycin-induced lung fibrosis model.
ACS Med Chem Lett
· 2026 Mar · PMID 41847633
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Stimulator of interferon genes (STING) is a transmembrane protein localized to the endoplasmic reticulum that serves as a pivotal sensor of intracellular DNA in innate immunity. Following the detection of pathogen-derive...Stimulator of interferon genes (STING) is a transmembrane protein localized to the endoplasmic reticulum that serves as a pivotal sensor of intracellular DNA in innate immunity. Following the detection of pathogen-derived or self-derived DNA in the cytosol, STING activates signaling cascades that promote the production of type I interferons and pro-inflammatory mediators. Beyond its well-established function in host defense, STING has emerged as an important regulatory node in antitumor immune surveillance, maintenance of immune tolerance, neuroinflammatory processes, and metabolic regulation. This patent overview outlines the design, synthesis, and potential therapeutic use of newly developed compounds aimed at treating disorders associated with dysregulated STING signaling.
Kumar R, Thian J, Toh JDW
… +12 more, Farzana N, Sun J, Kang C, Low SMC, Wee S, Lim Z, Gunaratne J, Loh HM, Kannan S, Verma CS, Chakraborty S, Hong W
ACS Med Chem Lett
· 2026 Mar · PMID 41847632
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Dysfunction of Hippo signaling resulting in elevated YAP/TAZ-TEAD activity is commonly associated with tumorigenesis and represents a therapeutic target for cancer. Drug resistance is a significant factor undermining the...Dysfunction of Hippo signaling resulting in elevated YAP/TAZ-TEAD activity is commonly associated with tumorigenesis and represents a therapeutic target for cancer. Drug resistance is a significant factor undermining the efficacy of cancer therapy. In this study, we identify a class of covalent small molecules with a vinyl sulfone warhead binding to the conserved cysteine of the TEAD and disrupting its interaction with YAP. These compounds (particularly CPD10 and CPD13) strongly inhibit proliferation and colony formation of cancer cell lines with altered Hippo signaling. Moreover, the TEAD dependency of gastric cancer cells enhance their sensitivity to CPD10 and CPD13 treatment. Importantly, the pan-TEAD inhibitors also promote synergistic cell death in EGFR- and KRAS mutant Non-Small Cell Lung Cancer (NSCLC) cells, which may eventually overcome drug resistance associated with the use of FDA-approved compounds. Therefore, we uncover a novel class of vinyl sulfone warhead-bearing pan-TEAD inhibitors with potential for treating gastric and mutant KRAS and EGFR lung cancers.
Herrick RM, Green SA, Rich S
… +3 more, Grandner JM, Huard K, Altman RA
ACS Med Chem Lett
· 2026 Feb · PMID 41728586
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Despite recent interest in -trifluoromethyl azoles, -α,α-difluoroalkyl azoles [(azole)N-CFR] remain understudied and underutilized in medicinal chemistry. To address this deficiency, we have conducted a comparative study...Despite recent interest in -trifluoromethyl azoles, -α,α-difluoroalkyl azoles [(azole)N-CFR] 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-CFR and their nonfluorinated matched molecular pairs (MMPs) that revealed fluorine-induced reductions in azole p , 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-CFR groups in drug optimization campaigns.
Stott AJ, Bürli RW, Doyle KJ
… +14 more, Dickson L, Hewer RC, Pickford P, Roberts MJ, Waters-Hall R, Wu Y, Zebisch M, Rangel V, Geitmann M, Matthews K, Brice NL, Carlton M, Dawson LA, Harvey JRM
ACS Med Chem Lett
· 2026 Feb · PMID 41704394
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Cluster of differentiation 38 (CD38) is a nicotinamide adenine dinucleotide (NAD)-consuming ectoenzyme abundantly expressed in brain regions involved in motor control and cognition. Given the central role of NAD in maint...Cluster of differentiation 38 (CD38) is a nicotinamide adenine dinucleotide (NAD)-consuming ectoenzyme abundantly expressed in brain regions involved in motor control and cognition. Given the central role of NAD in maintaining neuronal health, inhibition of CD38, resulting in NAD elevation, has emerged as a potential therapeutic approach for neurodegenerative diseases and age-associated cognitive decline. Herein, we report the rational, structure-guided optimization of a series of small-molecule CD38 inhibitors, culminating in the identification of , a potent, selective, and brain-penetrant tool molecule with favorable pharmacokinetic properties for advanced preclinical evaluation. We further disclose the first high-resolution X-ray crystal structure of the ADPRCD38 complex, revealing an uncompetitive binding mode. provides a molecular tool to investigate CD38 biology in neurodegeneration and supports the development of next-generation brain-penetrant CD38 inhibitors.
ACS Med Chem Lett
· 2026 Feb · PMID 41704393
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Provided herein are novel compounds as MALT1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.Provided herein are novel compounds as MALT1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.