Li Y, Song Z, Shi H
… +12 more, Zhao T, Chen J, Zhou X, Hu Q, Li X, Meng L, Song R, Sun Z, Li C, Haider A, Yuan H, Liang SH
ACS Med Chem Lett
· 2026 Feb · PMID 41704371
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Brain cholesterol homeostasis is critical for neuronal function and primarily regulated by cholesterol 24-hydroxylase (CYP46A1). Dysregulation of CYP46A1 has been implicated in Alzheimer's disease (AD) and Huntington's d...Brain cholesterol homeostasis is critical for neuronal function and primarily regulated by cholesterol 24-hydroxylase (CYP46A1). Dysregulation of CYP46A1 has been implicated in Alzheimer's disease (AD) and Huntington's disease (HD). Building on the clinically validated positron emission tomography (PET) tracer [F]-CHL-2205, we designed a deuterated isotopologue, CHL-2205 , targeting the amide -methyl group to enhance stability and enable mechanistic studies. Compound exhibited high CYP46A1 affinity (IC = 0.38 nM; = 0.22 nM). Radiosynthesis via copper-mediated [F]-fluorination afforded [F] in 31.5 ± 1.5% non-decay-corrected radiochemical yield and high molar activity (>95 GBq/μmol). Autoradiography and PET imaging in mice demonstrated robust brain uptake, heterogeneous regional distribution, and specific target engagement. Radiometabolite analysis confirmed that brain radioactivity was mainly attributable to intact [F], with a pharmacokinetics comparable to that of [F]-CHL-2205. [F] preserves [F]-CHL-2205 imaging performance and provides a deuterated PET tool for quantitative bioanalysis and integrated PET-deuterium metabolic imaging (DMI) studies of brain cholesterol metabolism.
Bubenik M, Mader P, Orlicky S
… +16 more, Perryman AL, Hamel M, Godbout C, Falgueyret JP, Kurinov I, Wong C, Gingras AC, Mamane Y, Zinda M, Morris SJ, Gallant M, Sfeir A, Black WC, Durocher D, Zimmermann M, Sicheri F
ACS Med Chem Lett
· 2026 Feb · PMID 41704370
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Human DNA polymerase θ (Polθ) is essential for microhomology-mediated end-joining (MMEJ) and represents a therapeutic vulnerability in homologous recombination (HR)-deficient cancers. Although reversible inhibitors of Po...Human DNA polymerase θ (Polθ) is essential for microhomology-mediated end-joining (MMEJ) and represents a therapeutic vulnerability in homologous recombination (HR)-deficient cancers. Although reversible inhibitors of Polθ have advanced into clinical development, covalent chemical probes remain unexplored. Analysis of a previously described structure of the reversible inhibitor bound to Polθ identified Cys2411 as an accessible residue 7.4 Å adjacent to the inhibitor binding site. Guided by X-ray crystallographic studies, we designed to reduce the separating distance between inhibitor and Cys2411 to 4.7 Å and then synthesized by incorporating a vinyl sulfone electrophile. Functional studies revealed efficient covalent linkage to Cys2411 ( = 11.6 s), while a high-resolution (2.0 Å) cocrystal structure validated the design strategy. These findings establish Cys2411 as a privileged site for covalent inhibitor development and provide a highly potent, selective chemical probe useful for investigating Polθ biology.
ACS Med Chem Lett
· 2026 Feb · PMID 41704369
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Off-target effects are usually undesirable in drug development, but for some PROTACs and other degraders, they may be advantageous. Specifically, this can be so when the activities of multiprotein complexes are more impo...Off-target effects are usually undesirable in drug development, but for some PROTACs and other degraders, they may be advantageous. Specifically, this can be so when the activities of multiprotein complexes are more important than just the targeted protein of interest.
ACS Med Chem Lett
· 2026 Feb · PMID 41704368
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Provided herein are novel compounds as LPAR1 inhibitors, pharmaceutical compositions, use of such compounds in treating systemic sclerosis, and processes for preparing such compounds.Provided herein are novel compounds as LPAR1 inhibitors, pharmaceutical compositions, use of such compounds in treating systemic sclerosis, and processes for preparing such compounds.
Helfstein DR, das Virgens MF, Rojas Moscoso JA
… +13 more, Zaminelli T, Toledo FT, Maia de Lima J, Medeiros LO, Marcello BA, Soares VM, Passos GR, de Padua SS, Wolf MEG, Carneiro LM, De Nucci G, Keppler AF, Mónica FZ
ACS Med Chem Lett
· 2026 Feb · PMID 41704367
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Benign prostatic hyperplasia (BPH) is a prevalent condition in aging men that negatively affects the quality of life. Current therapeutic strategies aim to reduce prostate size and smooth muscle contraction. In this stud...Benign prostatic hyperplasia (BPH) is a prevalent condition in aging men that negatively affects the quality of life. Current therapeutic strategies aim to reduce prostate size and smooth muscle contraction. In this study, five novel 4-oxazoline-centered compounds with potential phosphodiesterase (PDE) inhibitory activity were synthesized and tested for biochemical and pharmacological effects in isolated prostate cells and tissues. Among them, compound VIII exhibited inhibitory activity against PDE5 and two PDE4 isoforms in cell-free assays. Additionally, it relaxed isolated rat prostate tissue, enhanced nitric oxide-induced relaxation, and reduced contractile responses mediated by alpha-1 adrenoceptors. Moreover, compound VIII significantly inhibited the proliferation of a human hyperplastic prostate cell line, mimicking the effects of rolipram, a PDE4 inhibitor. With its dual inhibition of PDE4 and PDE5 and its ability to decrease both contraction and cell proliferation, compound VIII emerges as a promising candidate for further investigation as a potential treatment for BPH. Complementary molecular docking and conformational analyses provided a structural rationale for the observed activity trends, highlighting the role of hydroxyethyl substituent interactions with the PDE5A H-loop in modulating inhibitory potency. Taken together, the dual PDE4/PDE5 inhibition profile of compound VIII, combined with its favorable functional effects on smooth muscle tone and cell proliferation, identifies this scaffold as a promising starting point for further optimization toward BPH therapy.
ACS Med Chem Lett
· 2026 Feb · PMID 41704366
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Provided herein are novel compounds, pharmaceutical compositions, use of such compounds in treating hemoglobinopathies, and processes for preparing such compounds.Provided herein are novel compounds, pharmaceutical compositions, use of such compounds in treating hemoglobinopathies, and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 Feb · PMID 41704365
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The Werner Syndrome RecQ DNA helicase (WRN) plays a crucial role in DNA metabolism and genome stability. This patent collectively demonstrates the synthesis, composition and formulation about novel WRN inhibitors featuri...The Werner Syndrome RecQ DNA helicase (WRN) plays a crucial role in DNA metabolism and genome stability. This patent collectively demonstrates the synthesis, composition and formulation about novel WRN inhibitors featuring bicyclic heterocycles for cancer treatment.
Cox JB, Nair V, Mandal P
… +23 more, Reyna N, Tran T, Mustachio LM, Bardenhagen J, Fawver J, Shepard H, Hickey AM, Wu Q, Rodriguez C, Yu F, Phan P, Mendiola AJ, Johnson R, Thapar R, Johnson T, Jiang Y, Cross JB, Do MKG, Jones P, Marsalek J, Heffernan T, Soth MJ, Nagy E
ACS Med Chem Lett
· 2026 Feb · PMID 41704364
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NRAS G12D mutations are predominantly found in melanoma and hematologic malignancies, and there is an unmet need for developing targeted therapies against this oncogene. Herein, we describe the structure-guided developme...NRAS G12D mutations are predominantly found in melanoma and hematologic malignancies, and there is an unmet need for developing targeted therapies against this oncogene. Herein, we describe the structure-guided development of IACS-56676, a selective and potent NRAS G12D inhibitor useful as a tool compound for further studies of NRAS biology. The development process revealed key insights into gaining selectivity between NRAS and KRAS proteins. Notably, stabilization of the p-loop and substitution toward Leu 95 while maintaining key interactions with Asp12, Gly60, and Asp69 improved NRAS G12D potency and resulted in selectivity against wild-type KRAS/non-responder.
Zhang J, Yang X, Huang B
… +8 more, Xu Y, Geng S, Zhao M, Ding J, Zhang B, Shen Z, Dong X, Lin N
ACS Med Chem Lett
· 2026 Feb · PMID 41704363
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Pancreatic ductal adenocarcinoma (PDAC) exhibits a dismal prognosis, with limited therapeutic options beyond first-line chemotherapy. Extracellular signal-regulated kinase 5 (ERK5) represents a compelling therapeutic tar...Pancreatic ductal adenocarcinoma (PDAC) exhibits a dismal prognosis, with limited therapeutic options beyond first-line chemotherapy. Extracellular signal-regulated kinase 5 (ERK5) represents a compelling therapeutic target, particularly due to its compensatory role in sustaining proliferation and MYC stability following ERK1/2 inhibition in KRAS-mutant PDAC. To address the need for novel inhibitors, we implemented an integrated virtual screening workflow combining PSICHIC screening, KarmaDock, similarity analysis, molecular clustering, and manual selection. This strategy identified four structurally distinct ERK5-targeting candidates. Among these, compounds 1 and 2 inhibited ERK5 kinase activity with IC values of 416.4 and 991.3 nM, respectively. Compound 1 demonstrated potent antiproliferative effects on PDAC cell lines (PANC-1: IC = 1199.0 nM; MiaPaCa-2: IC = 62.5 nM; AsPC-1: IC = 199.9 nM). Molecular dynamics simulations revealed stabilization of the ERK5-compound 1 complex through hydrogen bonding with hinge residues MET-96 and ASP-94. These results establish compound 1 as a promising lead compound, providing a novel chemical scaffold for the development of ERK5-targeted therapies against PDAC.
ACS Med Chem Lett
· 2026 Feb · PMID 41704362
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The discovery of novel chemical entities for therapeutic use is a resource-intensive process. Given the constraints of drug discovery resources, it is crucial to allocate assets thoughtfully. This study identifies gaps i...The discovery of novel chemical entities for therapeutic use is a resource-intensive process. Given the constraints of drug discovery resources, it is crucial to allocate assets thoughtfully. This study identifies gaps in research organizations operating under resource limitations and proposes a pragmatic workflow tailored to these settings. This approach uses freely available tools to facilitate the determination of the clearance mechanism for the strategic advancement of chemical entities through data-informed decision-making processes while maximizing the efficiency.
Cho S, Szalai TV, El Gaamouch F
… +3 more, Bajusz D, Keserű GM, Gabr M
ACS Med Chem Lett
· 2026 Feb · PMID 41704361
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Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose loss-of-function variants increase Alzheimer's disease (AD) risk. While antibody-based agonists have shown promise, their tr...Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose loss-of-function variants increase Alzheimer's disease (AD) risk. While antibody-based agonists have shown promise, their translation is hindered by poor brain penetration and high cost. Here, we report the discovery and optimization of small-molecule TREM2 agonists through an AI-assisted virtual screening strategy. Deep docking of over five million purchasable compounds identified a structurally novel hit, , which engaged TREM2 with modest affinity. A SAR-by-catalog campaign led to the identification of as a potent binder. demonstrated favorable in vitro PK properties, including high solubility, passive BBB permeability, moderate metabolic stability, and minimal safety liabilities. Functionally, activated receptor-proximal signaling, inducing SYK phosphorylation in TREM2-expressing cells, and promoted microglial phagocytosis. Together, these findings establish as the most potent small-molecule TREM2 binder reported to date capable of driving protective microglial responses relevant to AD.
ACS Med Chem Lett
· 2026 Feb · PMID 41704360
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Provided herein are novel compounds as TIPARP inhibitors, pharmaceutical compositions, use of such compounds in treating head and neck squamous cell carcinoma (HNSCC), and processes for preparing such compounds.Provided herein are novel compounds as TIPARP inhibitors, pharmaceutical compositions, use of such compounds in treating head and neck squamous cell carcinoma (HNSCC), and processes for preparing such compounds.
ACS Med Chem Lett
· 2026 Feb · PMID 41704359
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Recent patent disclosures reveal convergent strategies to modulate IL-17-driven pathology through complementary chemical and delivery modalities. Acidic small-molecule inhibitors, PEGylated derivatives, and antibody-func...Recent patent disclosures reveal convergent strategies to modulate IL-17-driven pathology through complementary chemical and delivery modalities. Acidic small-molecule inhibitors, PEGylated derivatives, and antibody-functionalized lipid nanoparticles collectively address potency, exposure, and immune context. Together, these approaches outline an integrated framework for treating inflammatory diseases and immunosuppressive tumor microenvironments.
Pitasse-Santos P, Falcicchio M, Sahota R
… +5 more, Raza HG, Leney AC, Cowan RH, Hall G, Doveston RG
ACS Med Chem Lett
· 2026 Feb · PMID 41704358
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Molecular glues (MGs) offer a promising strategy for stabilizing protein-protein interactions (PPIs), particularly within the 14-3-3 protein family, which regulates diverse cellular processes and is implicated in many di...Molecular glues (MGs) offer a promising strategy for stabilizing protein-protein interactions (PPIs), particularly within the 14-3-3 protein family, which regulates diverse cellular processes and is implicated in many disease pathways. This study reports on the discovery of an aminoacrylamide MG () for 14-3-3 PPIs. Structure-activity relationship analysis using a fluorescence polarization (FP) assay revealed that both a basic amine and acrylamide moiety are essential for activity. However, further investigation using FP, mass spectrometry, and a thermal shift assay revealed that has a cysteine-independent mode of action, distinguishing it from other covalent 14-3-3 MGs. Furthermore, its activity is reliant on 14-3-3 dimerization suggesting that it targets the 14-3-3 dimer interface. Aminoacrylamide differentially affected interactions with ERα, LRRK2, and AHA2, suggesting that 14-3-3 dimerization plays an important role in 14-3-3 client recognition. These findings further validate the 14-3-3 dimer interface as a novel MG target and underscore the complexities of 14-3-3 molecular recognition and small-molecule modulation.
Colandrea VJ, Joshi-Pangu A, Nolte RT
… +10 more, Bledsoe RK, Ward P, Glancy J, Kowalski MD, Huff CA, Desai S, Nagilla R, Laping NJ, Axten JM, Evans KA
ACS Med Chem Lett
· 2026 Feb · PMID 41704357
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ISRIB reactivates protein synthesis for cells under stress through the stabilization of eukaryotic initiation factor 2 beta (eIF2B). We discovered that diaminoisohexides, derived from isomannide and isosorbide serve as a...ISRIB reactivates protein synthesis for cells under stress through the stabilization of eukaryotic initiation factor 2 beta (eIF2B). We discovered that diaminoisohexides, derived from isomannide and isosorbide serve as a bioisostere for the diamino cyclohexane core in ISRIB. These scaffolds conferred improved solubility but also showed activity for the human ether-a-go-go-related gene (hERG). Herein we describe our efforts to mitigate hERG activity while maintaining target potency. The first high resolution (2.25Å) X-ray cocrystal structure of the eIF2B (α,β,δ) complex with compound is reported, which can inform subsequent SAR.
Liu M, Tu Y, Xu W
… +6 more, Gao L, Wang K, Zhou Y, Xu T, Zhou Y, Zhou C
ACS Med Chem Lett
· 2026 Feb · PMID 41704356
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Casein kinase 1α (CK1α) is a serine/threonine kinase that plays a pivotal role in regulating p53 and other critical signaling pathways and is intimately involved in tumor initiation and progression. Inhibition of CK1α ha...Casein kinase 1α (CK1α) is a serine/threonine kinase that plays a pivotal role in regulating p53 and other critical signaling pathways and is intimately involved in tumor initiation and progression. Inhibition of CK1α has been demonstrated to be a promising therapeutic strategy for certain types of cancers such as acute myeloid leukemia (AML). In this study, we designed and synthesized a series of novel CK1α inhibitors bearing a 7-pyrrolo-[2,3-]-pyrimidine scaffold. The structure-activity relationship was systematically summarized, and notably, compound exhibited potent inhibitory activity against CK1α with an IC of 10.96 nM, representing a 9-fold increase in potency as compared to BTX-A51, the only CK1α inhibitor currently in clinical development. Additionally, compound displayed favorable selectivity across a panel of kinases. It also dose-dependently stabilized p53 protein and effectively inhibited the growth of MV4-11 cells. Further optimization of may provide promising CK1α inhibitors with desirable drug-like properties for cancer treatment.
ACS Med Chem Lett
· 2026 Feb · PMID 41704355
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This patent highlight describes the development and evaluation of novel pyridopyrazine analogs as potent inverse agonists for G protein-coupled receptor 6 (GPR6). It discloses synthetic methods and pharmacological proper...This patent highlight describes the development and evaluation of novel pyridopyrazine analogs as potent inverse agonists for G protein-coupled receptor 6 (GPR6). It discloses synthetic methods and pharmacological properties of these new GPR6 modulators.
ACS Med Chem Lett
· 2026 Feb · PMID 41704354
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Provided herein are novel compounds as CX3CR1 modulators, pharmaceutical compositions, use of such compounds in treating cardiovascular diseases, and processes for preparing such compounds.Provided herein are novel compounds as CX3CR1 modulators, pharmaceutical compositions, use of such compounds in treating cardiovascular diseases, and processes for preparing such compounds.
Biernacki K, Ciupak O, Daśko M
… +11 more, Grobelna A, Mirocki A, Rak J, Czubak P, Martyna A, Kubiński K, Masłyk M, Szwarc-Karabyka K, Kwaśnik M, Rachoń J, Demkowicz S
ACS Med Chem Lett
· 2026 Feb · PMID 41704353
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A novel series of 3,5-disubstituted 1,2,4-oxadiazole sulfamates was synthesized and evaluated as steroid sulfatase (STS) inhibitors. Molecular docking predicted high affinity (binding energies of up to -8.9 kcal·mol), of...A novel series of 3,5-disubstituted 1,2,4-oxadiazole sulfamates was synthesized and evaluated as steroid sulfatase (STS) inhibitors. Molecular docking predicted high affinity (binding energies of up to -8.9 kcal·mol), often surpassing the reference Irosustat. Biological evaluation confirmed potent inhibition; compound reduced enzymatic STS activity to 3.5% at 10 μM. In JEG-3 cells, the most potent derivative, , exhibited an IC of 6.64 nM, comparable to that of Irosustat (4.19 nM). Structure-activity relationship analysis revealed that the substitution pattern of the oxadiazole heterocycle plays a decisive role in determining biological activity. Shifting the aryl-sulphamate pharmacophore between positions 3- and 5- of the 1,2,4-oxadiazole heterocycle is crucial for maintaining high biological activity. These findings establish 3,5-disubstituted 1,2,4-oxadiazole sulfamates as promising leads for treating hormone-dependent cancers.