Bai J, Shi H, Chen J
… +5 more, Tian H, Liang J, Chen B, Li J, Fang L
Bioorg Med Chem Lett
· 2026 Mar · PMID 41371309
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Extracellular and cell membrane proteins are critical for maintaining physiological homeostasis and the abnormal expression of these proteins cause various diseases. Consequently, the development of targeted degradation...Extracellular and cell membrane proteins are critical for maintaining physiological homeostasis and the abnormal expression of these proteins cause various diseases. Consequently, the development of targeted degradation strategy for these proteins represents a significant therapeutic opportunity. Leveraging cell-penetrating peptide (CPP)-induced endocytosis and lysosomal delivery, bicyclic CPP-mediated lysosome-targeting chimeras (CPPTACs) were developed to selectively degrade extracellular and cell surface proteins. Constructed by the conjugation of a bicyclic CPP containing the KRK motif with different target protein-binding molecules, these bicyclic peptide-based CPPTACs demonstrate the ability to enhance cellular uptake and facilitate the rapid degradation of protein targets via the endo-lysosomal pathway. These findings support the advancement of bicyclic peptide-based CPPTACs in pharmaceutical drug discovery.
Bioorg Med Chem Lett
· 2026 Mar · PMID 41365400
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The surge in fungal infection-related mortality worldwide is being caused by drug resistance to well-established antifungals such azole derivatives (bifonazole, fluconazole, miconazole, and clotrimazole). Finding novel m...The surge in fungal infection-related mortality worldwide is being caused by drug resistance to well-established antifungals such azole derivatives (bifonazole, fluconazole, miconazole, and clotrimazole). Finding novel molecules that are structurally different to these could be a useful tactic to get over medication resistance that is currently on the market. In an effort to develop highly potent non-resistance antifungal agents, we reported a series of compounds with benzothiazole, S-benzyl-2,4-isodithiobiuret and thiourea derivatives of 1-hepta-O-benzoyl-β-d-maltose NPs and their antifungal activity against the most infectious fungal strain Candida albicans. Numerous analogues among the synthesized compounds have shown potent antifungal activity. All the synthesized compounds were tested in vitro for determining their anticandidal activity. Almost all the compounds were found to be highly potent than established antifungal drugs (MIC ¼ 0.25-0.125 mg mL) against Candida albicans strain. An in silico molecular docking study was also performed to comprehend the mode of action of the active compounds towards prospective target 1EA1 binding protein.
Akdağ M, Çam MG, Ergen D
… +3 more, Demir Y, Beydemir Ş, Özçelik AB
Bioorg Med Chem Lett
· 2026 Mar · PMID 41354255
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Diabetes mellitus is a chronic metabolic disorder associated with microvascular complications such as neuropathy, nephropathy, and retinopathy. Two complementary therapeutic strategies are targeting the polyol pathway vi...Diabetes mellitus is a chronic metabolic disorder associated with microvascular complications such as neuropathy, nephropathy, and retinopathy. Two complementary therapeutic strategies are targeting the polyol pathway via aldose reductase (ALR2) inhibition and controlling postprandial hyperglycemia through α-glucosidase (α-Glu) inhibition. In this study, we designed and synthesized a novel series of eight pyridazinone derivatives incorporating thiosemicarbazide, S-triazole, and 1,3,4-thiadiazole 2-amine scaffolds. These compounds were evaluated for their dual inhibitory potential against ALR2 and α-Glu enzymes using in vitro kinetic assays. Among the tested molecules, compound 4, bearing a fluorinated thiadiazole moiety, exhibited the most potent activity with K values of 0.094 μM (ALR2) and 0.171 μM (α-Glu), surpassing standard inhibitors epalrestat and acarbose, respectively. Structure-activity relationship analysis indicated that fluorine substitution and a 1,3,4-thiadiazole core significantly enhance dual inhibitory potency. Docking studies further confirmed strong binding interactions within the active site of ALR2, supported by π-π stacking, hydrogen bonding, and hydrophobic interactions. These findings suggest that halogenated pyridazinone derivatives, especially fluorinated thiadiazole analogs, represent promising dual inhibitors for managing hyperglycemia and preventing diabetic complications. The dual-targeting approach demonstrated in this work offers a rational design framework for future antidiabetic drug development.
Kim Y, Sun J, Lee K
… +6 more, Kim S, Lee D, Park B, Lee Y, Hwang I, Ryu JS
Bioorg Med Chem Lett
· 2026 Mar · PMID 41354254
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Bruton's tyrosine kinase (BTK) has emerged as a validated therapeutic target for B-cell malignancies and autoimmune disorders, and covalent BTK inhibitors have demonstrated remarkable clinical efficacy. However, because...Bruton's tyrosine kinase (BTK) has emerged as a validated therapeutic target for B-cell malignancies and autoimmune disorders, and covalent BTK inhibitors have demonstrated remarkable clinical efficacy. However, because of concerns regarding their off-target effects and safety profiles, there is research interest in developing noncovalent, reversible inhibitors. Herein, we report the design, synthesis, and biochemical evaluation of novel imidazo[4,5-b]pyridine derivatives as noncovalent BTK inhibitors. Through a concise three-step synthetic route, we prepared 16 structurally diverse analogs (6a-p) bearing various substituents on the imidazole scaffold. The results of biochemical evaluation showed that 6b, 6o, and 6p are the most potent inhibitors, with IC₅₀ values of 1.14, 1.54, and 2.46 μM, respectively. The results of structure-activity relationship studies revealed that 2,4-dihydroxyphenyl substitution on the A-ring and extended functionalities (morpholinomethyl or 4-acetamido group) on the B-ring significantly enhanced the inhibition of BTK. The results of molecular docking studies elucidated key binding interactions and showed that the hydroxyl groups form hydrogen bonds with the Thr474 gatekeeper residue and the Met477 hinge region residue, whereas B-ring substituents extend toward the DFG motif. The preliminary kinase selectivity profiling of 6b against 39 kinases demonstrated promising selectivity, with significant inhibition observed primarily for BTK and c-Src. Although these compounds show moderate potency compared with clinically approved BTK inhibitors, their noncovalent, reversible nature offers potential advantages with regard to selectivity, toxicity, and pharmacological effects. Moreover, these compounds represent valuable starting points for further optimization toward developing novel therapeutics for B-cell malignancies and autoimmune disorders with potentially improved safety profiles for long-term treatment.
Bioorg Med Chem Lett
· 2026 Mar · PMID 41319815
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NASH represents an increasingly prevalent chronic liver disease, and TZDs are investigated as a potential therapeutic strategy. However, the inherent enolic structure of TZDs leads to enantiomeric instability and racemiz...NASH represents an increasingly prevalent chronic liver disease, and TZDs are investigated as a potential therapeutic strategy. However, the inherent enolic structure of TZDs leads to enantiomeric instability and racemization, often requiring their use as racemic mixtures. We here report the development of a novel TZD-derivative, 9, in which deuterium incorporation at the chiral center was strategically employed to enhance stereoisomeric stability while maintaining the desired pharmacological profile. In vitro, compound 9 displayed robust activity, with an EC of 0.32 ± 0.04 μM in HEK293 cells. Pharmacokinetic analysis revealed a C of 1693 ± 339 ng/mL and an AUC of 8711 ± 871 ng∙h/mL. Furthermore, compound 9 demonstrated superior therapeutic efficacy in a mouse model of NASH. These findings suggest that the compound 9 represents a promising therapeutic candidate for NASH.
Yi Y, Sun Y, Zhang X
… +4 more, Xin J, Zhao F, Zhu W, Liu S
Bioorg Med Chem Lett
· 2026 Mar · PMID 41317750
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Liver cancer represents a major global health challenge, significantly impacting populations both in China and worldwide. Alpinetin (ALP), extracted from the ginger plant cardamom, has been shown to possess significant a...Liver cancer represents a major global health challenge, significantly impacting populations both in China and worldwide. Alpinetin (ALP), extracted from the ginger plant cardamom, has been shown to possess significant anti-liver cancer activity. However, its solubility and mechanism of action remain unclear, hindering its further development and application. Heat shock protein 70 (HSP70) has been proven to be a potential target for the treatment of liver cancer. Based on rational drug design principles, ALP was conjugated with specific pharmacophores through oxime linkages to yield novel compounds, aiming to reduce toxicity and enhanced activity. Thus, representative compounds 1a and 1b were obtained. Then, the preliminary mechanism of action was further investigated. Western blot analysis results indicate that compounds 1a and 1b could inhibit the expression of HSP70 protein in HepG2 liver cancer cells. Cell apoptosis data indicate that the synthesized compounds exert anticancer activity by inducing apoptosis. Therefore, this study suggests that ALP and its derivatives may become promising drugs for exerting anti liver cancer effects by regulating the expression of HSP70 protein.
Bioorg Med Chem Lett
· 2026 Mar · PMID 41297684
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Cancer maintains to be a major worldwide health epidemic, and despite breakthroughs in targeted agents, immunotherapy, chemotherapy, and surgery, considerable limitations persist. These comprise therapeutic resistance, d...Cancer maintains to be a major worldwide health epidemic, and despite breakthroughs in targeted agents, immunotherapy, chemotherapy, and surgery, considerable limitations persist. These comprise therapeutic resistance, dose-limiting toxicities, late diagnosis, and microenvironmental barriers, including hypoxia and poor perfusion. The spatiotemporally regulated, locally activated cytotoxicity that photodynamic therapy (PDT) and sonodynamic therapy (SDT) provide has made them appealing substitutes. They may also be used in conjunction with immunotherapy and imaging. SDT uses ultrasound to allow for deeper penetration and partial oxygen independence, whereas PDT uses light to activate photosensitisers. Both approaches produce radical intermediates and reactive oxygen species (ROS), which harm vital biomolecules and activate several pathways leading to programmed cell death, hence decreasing the probability of resistance. However, SDT necessitates the optimisation of acoustic parameters and verified clinical protocols, while PDT is limited by oxygen reliance and poor light penetration. Transition metal complexes, especially those of iridium (III) and rhenium (I), offer special benefits for PDT and SDT because of their intrinsic luminescence, effective triplet-state creation, high spin-orbit coupling, and variable photophysical characteristics. Their translational potential is being advanced by rational design tactics such as theranostic pairing, red/NIR and two-photon activation, nanocarrier integration, and Type I biasing for hypoxia tolerance. With continuous attempts to standardise dosimetry and sensitiser design, SDT is still in the early phases of evaluation, whereas PDT is clinically established. This study highlights Ir and Re complexes as adaptable next-generation sensitisers that could broaden the therapeutic reach of externally activated cancer medicines by synthesising molecular insights, representative chemical classes, and translational obstacles.
Bioorg Med Chem Lett
· 2026 Feb · PMID 41276142
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In this study, 2,4,6-trisubstituted pyridine derivative Z-001 containing adamantyl moiety was designed through the hybridization strategy of LXH254 and adamantane. A new and effective synthetic route was established to a...In this study, 2,4,6-trisubstituted pyridine derivative Z-001 containing adamantyl moiety was designed through the hybridization strategy of LXH254 and adamantane. A new and effective synthetic route was established to achieve the synthesis of Z-001 through four step reactions, starting from commercially available 3-bromo-4-methylaniline and (2,6-dichloropyridin-4-yl) boronic acid. Besides, Z-001 was evaluated inhibitory activity against B-RAF kinase with IC value of 37.80 nM by ADP-Glo kinase assay, and it was found that Z-001 was a more potent B-RAF inhibitor than Vemurafinib (IC = 78.52 nM). Furthermore, molecular docking simulations showed that Z-001 bound to DFG-out/C-helix-in conformation in the B-RAF kinase, and formed three hydrogen bonds with GLU501, ASP594 and CYS532, respectively. It was worth noting that the adamantane alcohol of Z-001 was very suitable for matching the cavities near the solvent exposed region, which was filled with adamantyl moiety and effectively utilized in the docking model. The binding mode between Z-001 and B-RAF kinase provided a reasonable explanation for Z-001 as a potential B-RAF kinase inhibitor.
Zhu J, Gutkin S, Chen S
… +4 more, Su SP, Phan H, Shabat D, Bogyo M
Bioorg Med Chem Lett
· 2026 Mar · PMID 41274465
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The cysteine cathepsins are a family of proteases that are widely expressed in diverse cell types. However, because their activity is highly upregulated at sites of inflammation, they are ideal targets for imaging a rang...The cysteine cathepsins are a family of proteases that are widely expressed in diverse cell types. However, because their activity is highly upregulated at sites of inflammation, they are ideal targets for imaging a range of disease pathologies including cancer, atherosclerosis, fibrosis and others. While significant advances have been made in generation of activatable 'smart' probes for cathepsin activity, virtually all of these agents use fluorescent reporters which require a laser light source to induce a signal from the probe. We describe here the development and application of chemiluminescent probes for imaging cysteine cathepsin activity in cells and tissues. These probes provide rapid signal generation with low background in cells and tissues without the need for a light source. We demonstrate that a cathepsin probe containing an optimal peptide sequence can be used topically to detect activity in tumor tissues, demonstrating the potential value of this approach for real-time diagnosis of cancer as well as other conditions involving inflammation.
Sun T, Li Z, Xiao B
… +6 more, Yang J, Han M, Zhang J, Liu S, Ma J, Wang P
Bioorg Med Chem Lett
· 2026 Feb · PMID 41265581
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Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated Tau tangles, and neuronal loss, lacks effective disease-modifying therapies. Herbal medic...Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated Tau tangles, and neuronal loss, lacks effective disease-modifying therapies. Herbal medicines like Atractylodes macrocephala (AM) offer promising candidates for AD drug development, given their structural diversity and neuroprotective potential. Our prior work involved systematic phytochemical isolation of AM and preliminary anti-AD activity evaluation, through which we identified atractylenolide A1 as a neuroprotective lead. To further optimize efficacy, we herein synthesized a small series of novel atractylenolide derivatives via structural modification of A1's exocyclic. Among derivatives, B7 exhibited the broadest activity such as inhibiting self- and Cu-induced Aβ aggregation, protecting neurons and microglia, and mitigating Aβ toxicity in vivo. The exocyclic ester of A1 proves a viable modification site, with B7 emerging as a promising multi-target lead for AD therapy.
Fukuda T, Nishi T, Ishiyama T
… +8 more, Kitazawa R, Ishii K, Takahashi S, Kawabata Y, Yamaguchi K, Baba D, Ito S, Tanaka N
Bioorg Med Chem Lett
· 2026 Feb · PMID 41265580
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The inhibition of hypoxia-inducible factor prolyl hydroxylase domain proteins (HIF-PHDs) represents a promising strategy for treating renal anemia. We identified a hydroxypyrimidine core with HIF-PHD inhibitory activity...The inhibition of hypoxia-inducible factor prolyl hydroxylase domain proteins (HIF-PHDs) represents a promising strategy for treating renal anemia. We identified a hydroxypyrimidine core with HIF-PHD inhibitory activity based on a fragment-based drug discovery strategy using various X-ray crystal structures of the HIF-PHD2 domain in complex with a compound. We discovered brand-new amino succinic acid scaffolds by combining the structural information on the crystal structure complexed with 6-acetamide nicotinic acid. DS79540454 exhibits high enzyme inhibitory activity equivalent to that of DS-1093a, which has advanced to clinical trials.
Gryniukova A, Rogalsky S, Borysko P
… +3 more, Hodyna D, Kovalishyn V, Metelytsia L
Bioorg Med Chem Lett
· 2026 Feb · PMID 41248813
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In the context of rapidly developing resistance caused by mutations in genes that control oncogenic pathways and cancer cell survival, as well as to known and widely accessible antitumor drugs, combined strategies are cr...In the context of rapidly developing resistance caused by mutations in genes that control oncogenic pathways and cancer cell survival, as well as to known and widely accessible antitumor drugs, combined strategies are critical as a modern approach to cancer therapy. The in vitro results from a study of several long-chain N-alkylimidazole derivatives, combined with the known anticancer drugs doxorubicin and cisplatin, using cell lines of chronic myeloid leukemia K562, neuroblastoma SK-N-DZ, and mammary gland adenocarcinoma MCF7, show that the imidazolium-based ionic liquids 1-dodecyl-3-methylimidazolium chloride (IMCC-Cl), 1-dodecyloxycarbonylmethyl-3-methylimidazolium chloride (IMCCHCOOC-Cl), and, to a lesser extent, lysosomotropic detergent 1-dodecylimidazole (IMC) consistently stand out as the most promising across all cell lines. IMCC-Cl demonstrated significant reductions in cisplatin and doxorubicin doses, along with enhanced cytotoxic effects, in both K562 and SK-N-DZ cells, with DRI values of 4.36 μM for cisplatin and 15.00 μM for doxorubicin. IMCCHCOOC-Cl showed high DRI and synergism in MCF7 cells and moderate activity in SK-N-DZ cells. IMCC-Cl and IMCCHCOOC-Cl appear to be promising candidates for the development and evaluation of their combinatorial anticancer effects.
Zeng T, Yu W, Gu C
… +5 more, Fu JG, Asgari M, Li Y, Qian F, Feng CG
Bioorg Med Chem Lett
· 2026 Feb · PMID 41242349
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Mast cell degranulation plays a central role in IgE-driven allergic diseases, yet the therapeutic options for stabilizers remain limited. Rosinane diterpenoids, a class of natural polyphenols known for their anti-inflamm...Mast cell degranulation plays a central role in IgE-driven allergic diseases, yet the therapeutic options for stabilizers remain limited. Rosinane diterpenoids, a class of natural polyphenols known for their anti-inflammatory properties, represent an attractive source for novel anti-allergic compounds. Dehydroabietic acid (DHAA), a member of this class, exhibits diverse biological activities, yet its potential in mast cell regulation remains unexplored. In this study, we designed and synthesized a series of novel DHAA derivatives. We evaluated their anti-allergic effects in IgE/antigen-stimulated bone marrow-derived mast cells (BMMCs), and found that compound 4f significantly and dose-dependently inhibited IgE-mediated Ca influx and suppressed mast cell degranulation. Moreover, in vivo studies demonstrated that compound 4f effectively attenuated passive cutaneous anaphylaxis in mice and reduced vascular leakage. These findings indicate that compound 4f represents a novel mast cell stabilizer and provides a promising structural scaffold for developing new anti-allergic therapeutics.
Moukha-Chafiq O, Bratton LD, Karyakarte SD
… +8 more, Keith K, Martinez-Gzegozewska Y, Sarngadharan SC, Rasmussen L, Bostwick B, Pathak AK, Whitley R, Augelli-Szafran CE
Bioorg Med Chem Lett
· 2026 Feb · PMID 41242348
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We report the synthesis and evaluation of novel prodrugs of 6-azacytidine (6-AzaCyd) to identify potent and bioavailable inhibitors of influenza A viruses. Prodrug N-2-propylpentanamide 6-AzaCyd 6a was identified, throug...We report the synthesis and evaluation of novel prodrugs of 6-azacytidine (6-AzaCyd) to identify potent and bioavailable inhibitors of influenza A viruses. Prodrug N-2-propylpentanamide 6-AzaCyd 6a was identified, through a nucleoside prodrug strategy, with a promising potency profile [H1N1-EC = 2.6 μM, VTR = 3 at 10 μM; H3N2-EC = 3.5 μM, VTR = 2.8 at 10 μM in MDCK cells; EC = 2.1 μM from cap snatching polymerase U2-PB2 assay; cytotoxicity CC > 40 μM in A549 cells; CC > 20 μM in MDCK cells] and an acceptable absorption, distribution, metabolism and excretion (ADME) profile [mouse liver microsome (MLM) t = 105 min, human liver microsome (HLM) t = 65 min, Solubility = 77 μM]. Compound 6a also exhibited acceptable pharmacokinetic properties via intraperitoneal (i.p.) route of administration. The details for the synthesis of 6-AzaCyd prodrugs and anti-influenza A activity are described herein.
Khan A, Alzahrani AR, Rehman ZU
… +5 more, Zaidi SHH, Hai A, Al-Bazi MM, Banjabi AA, Imran M
Bioorg Med Chem Lett
· 2026 Feb · PMID 41241079
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The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-α) plays a substantial role in the advancement of various autoimmune diseases and is mostly suppressed by the monoclonal antibody adalimumab (Humira). This...The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-α) plays a substantial role in the advancement of various autoimmune diseases and is mostly suppressed by the monoclonal antibody adalimumab (Humira). This study utilized a rational in-silico method to design and optimize adalimumab Fab mutants with enhanced TNF-α binding affinity. A total of 512 mutants were produced with a Python automation script and FoldX. Eight mutants were selected for further analysed based on their stability (ΔG). The humanness ratings of the chosen variations were computed, demonstrating that they preserved similar human-like attributes. The anticipated expression in E. coli was elevated, with values between 0.93 and 0.94, as evidenced by the solubility analysis, which was analogous to the control (adalimumab) result of 0.94. Molecular docking revealed that all mutants displayed negligible RMSD values (≤ 0.001 Å) and uniform interface residues. FreeSASA and MM/GBSA studies were conducted to identify the top three candidates (Antibody-98, Antibody-354, and Antibody-374), which were subsequently confirmed by molecular dynamics simulations. Antibody-374 (yellow) and Antibody-98 (green) exhibit negligible variations (∼0.2-0.3 nm). Relative to the control, all three mutants demonstrated an elevation in total buried surface area (BSA), with Antibody-354 displaying the greatest measurement (5434.06 Å). Antibody-98 exhibited 14-15 hydrogen bonds, which were sustained at about 8-10 bonds for the majority of the simulation. Antibody-354 exhibited a range of 6-8 number of hydrogen bonds, while Antibody-374 had a robust contact with 6-10 hydrogen bonds. In the binding free energy examination utilizing MM/GBSA, Antibody-374 exhibited the most advantageous ΔG (-36.67 kcal/mol), succeeded by Antibody-98 (-30.07 kcal/mol) and Antibody-354 (-25.47 kcal/mol). These antibodies surpassed the wild-type docked model (-24.80 kcal/mol) and the native crystal complex (-25.46 kcal/mol). The enhancements were ascribed to particular point mutations, namely G28S, R90E, Y96W (light chain), and W53Y/F, L102I/V (heavy chain), which augmented molecular interactions and complex stability. This study demonstrated the capability of computational antibody engineering to generate Fab variants with enhanced binding affinity and stability for TNF-α. These findings thus offer significant insights for the advancement of future biologic therapies.
Mamai A, Morshed MM, Prakesch M
… +24 more, Poda G, Subramanian P, Chau AM, Watson IDG, Joseph B, Wilson B, Morin JA, Marcellus R, Theriault B, Mohammed M, Abibi A, Chan M, Kiyota T, Aman A, Subramaniam R, Strathdee C, Winston J, O'Meara J, Kuntz D, Pomroy NC, Uehling D, Isaac M, Privé GG, Al-Awar R
Bioorg Med Chem Lett
· 2026 Feb · PMID 41241078
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Diffuse Large B-Cell Lymphoma (DLBCL) is one of the most aggressive forms of lymphoid malignancies. About 40 % of patients eventually relapse and succumb to the disease within 5 years after diagnosis, underscoring the ne...Diffuse Large B-Cell Lymphoma (DLBCL) is one of the most aggressive forms of lymphoid malignancies. About 40 % of patients eventually relapse and succumb to the disease within 5 years after diagnosis, underscoring the need for new treatment modalities. B-Cell Lymphoma 6 protein (BCL6) is a repressive transcription factor that is dysregulated in about 40 % of DLBCLs. As a rationale for pursuing BCL6 as a drug target, disrupting complexes between this protein and its co-repressors is thought to mitigate the downstream oncogenic effects of this pathway. However, drugging transcription factors presents a formidable undertaking since targeting protein-protein interactions has historically been challenging. In this study, we used X-ray structures of BCL6-SMRT (a silencing mediator for retinoid or thyroid-hormone receptors, also known as the nuclear receptor co-repressor 2, NCOR2) peptide and compound 79-6 to conduct a virtual screen of a library of 5.2 million compounds. Through this exercise, we identified the pyrrolopyridone 3 as a viable hit, which in turn led to the identification of pyrrolopyrimidone lead compound 4. The X-ray crystal structure of 4 bound to the BTB (Broad-Complex, Tramtrack, and Bric à brac) domain of BCL6 revealed a large back pocket as well as a left-hand channel adjacent to the ligand that could be leveraged to optimize these compounds. Sulfonamide side chains were therefore introduced to target this space, leading to compounds 11d and 11e having sub-micromolar binding to the BTB domain of BCL6.
Ahn SA, Ishida K, Watanabe R
… +3 more, Imai T, Yamasaki M, Tomizaki KY
Bioorg Med Chem Lett
· 2026 Feb · PMID 41232784
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Gold nanorods (GNRs) can perform photothermal energy conversion by absorbing near-infrared (NIR) light and converting it to heat, and are therefore promising for applications in photothermal cancer therapy. However, to s...Gold nanorods (GNRs) can perform photothermal energy conversion by absorbing near-infrared (NIR) light and converting it to heat, and are therefore promising for applications in photothermal cancer therapy. However, to synthesize these nanorods, the highly cytotoxic compound cetyltrimethylammonium bromide (CTAB) is required. In the present study, to overcome this difficulty, we developed a method for synthesizing CTAB-free nanocrystals in the form of gold nanoworms (GNWs) using a self-assembling peptide exhibiting a positively-charged nuclear localization signal (NLS) sequence. We investigated the photothermal conversion performance of the GNWs and their ability to induce cell death under NIR irradiation. Based on transmission electron microscopy observations, the NLS-GNWs were determined to be approximately 80 nm in length and 9 nm in width. Their photothermal conversion efficiency was estimated to be 0.27 ± 0.06. Interestingly, in the absence of NLS-GNWs, following three cycles of NIR light exposure for 5 min at an intensity of 5 W/cm separated by 10 min intervals, no significant change in cytotoxicity of HeLa cells was observed compared with the control. However, in the presence of NLS-GNWs, the cell viability after the first, second and third cycles was approximately 25 %, 18 % and 10 %, respectively. The intracellular localization of NLS-GNWs was also investigated using fluorescein labelled-NLS-GNWs, and it was found that many of the GNWs were present at the nuclei of the HeLa cells. The positively-charged NLS-GNWs are thought to have been attracted to the relatively acidic surfaces of the cancer cells.
Tokuyama A, Yamashita Y, Maeda R
… +8 more, Akiyama T, Takada Y, Yoshino R, Kato H, Yu S, Itoh Y, Tachibana M, Suzuki T
Bioorg Med Chem Lett
· 2026 Feb · PMID 41218699
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Heterochromatin protein 1 (HP1), one of the epigenetic "reader" proteins, recognizes trimethylated lysine 9 of histone H3 (H3K9me3) to repressively regulate gene transcription by promoting chromatin aggregation. Overexpr...Heterochromatin protein 1 (HP1), one of the epigenetic "reader" proteins, recognizes trimethylated lysine 9 of histone H3 (H3K9me3) to repressively regulate gene transcription by promoting chromatin aggregation. Overexpression of HP1 plays a role in the growth of various cancer cells. Therefore, inhibiting its interaction with H3K9me3 is considered a promising therapeutic strategy for cancer treatment. This study aimed to identify small molecules that bind to HP1 and inhibit the HP1/H3K9me3 interaction. We performed in silico screening of the compounds from the Osaka University Library and selected 61 virtual hit compounds. As a result of in vitro evaluation of the hits by an HP1/H3K9me3 interaction inhibition assay, we identified compound 1, which exhibited 36 % inhibitory activity at 100 μM. Furthermore, the structural optimization of 1 led to the identification of (R)-18 (IC: 18.1 μM)-a novel small molecule that inhibits the HP1/H3K9me3 interaction.
Tang X, Pang J, Huang Y
… +3 more, Cui J, Gan C, Liu Z
Bioorg Med Chem Lett
· 2026 Mar · PMID 41218698
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Three novel classes of coumarin [3,4]-fused tetrahydroheterocyclics were synthesized in one step using donor-acceptor cyclopropane diesters as 1,3-dipoles via a facile [3 + 2]/[3 + 3] annulation/lactonization strategies....Three novel classes of coumarin [3,4]-fused tetrahydroheterocyclics were synthesized in one step using donor-acceptor cyclopropane diesters as 1,3-dipoles via a facile [3 + 2]/[3 + 3] annulation/lactonization strategies. The antibacterial activities of these compounds were evaluated against two species of animal-derived pathogenic bacteria (Staphylococcus aureus, Escherichia coli) and three species of plant-derived pathogenic bacteria (Xanthomonas citri, Pseudomonas oryzae, Fusarium oxysporum). The results showed that coumarin-fused tetrahydrofuran compounds (e.g., 3aa, 3ac and 3ae) exhibited significant selective antibacterial activity against Staphylococcus aureus with a minimum inhibitory concentration (MIC) of 2 μg/mL, while no obvious inhibitory effect was observed against other tested strains. Coumarin-fused tetrahydropyridazines (e.g., 7ad, 7ae, 7ah and 7ag) displayed excellent antibacterial activity against Pseudomonas oryzae and Fusarium oxysporum, with an MIC value of 2 μg/mL for all, and their antibacterial effect was significantly superior to that of osthol (the positive control). In contrast, coumarin-fused tetrahydro-1,2-oxazines showed relatively weak antibacterial activity, only compounds 5 ac and 5ak exerted moderate inhibitory effects on Staphylococcus aureus and Pseudomonas oryzae, both with an MIC value of 4 μg/mL. The findings of this study provide an important theoretical basis for the design and synthesis of novel coumarin-fused tetrahydroheterocyclic antibacterial agents.
Bioorg Med Chem Lett
· 2026 Feb · PMID 41218697
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Target-selective and site-specific incorporation of a desired functionality into a membrane protein endogenously expressed in cells is a great challenge in chemical biology. Here, we describe a versatile strategy for cov...Target-selective and site-specific incorporation of a desired functionality into a membrane protein endogenously expressed in cells is a great challenge in chemical biology. Here, we describe a versatile strategy for covalent chemical modification of short peptide tag-fused membrane proteins expressed in cells. This method is based on the recognition-driven reaction of a lysine-containing short histidine tag (KH6 or H6K sequence) and a binuclear nickel (II)-nitrilotriacetic acid (BisNi-NTA) complex probe containing a lysine-reactive N-acyl-N-alkyl sulfonamide (NASA). Our reactive peptide tag system enabled the selective modification of cell-surface proteins with affinity tags or fluorescent probes through a simple one-step protocol. In this study, we fused the KH6 or H6K tag to cell-surface proteins such as Neuroligin-1, epidermal growth factor receptor (EGFR), and Neurexin-1β, and achieved selective chemical modification of these proteins in live cells. Furthermore, we demonstrated that our short peptide tag allows efficient labeling not only when introduced at the protein termini but also when incorporated internally.