Liu W, Du S, Wang M
… +4 more, Sun S, Wang L, Liu J, Wang S
Bioorg Med Chem Lett
· 2026 Jul · PMID 41786054
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FLT3 mutations, including internal tandem duplications (ITD) and tyrosine kinase domain (TKD) variants, are key drivers of acute myeloid leukemia (AML) and represent attractive therapeutic targets. Guided by a scaffold-h...FLT3 mutations, including internal tandem duplications (ITD) and tyrosine kinase domain (TKD) variants, are key drivers of acute myeloid leukemia (AML) and represent attractive therapeutic targets. Guided by a scaffold-hopping strategy based on G-749 (denfivontinib), a series of quinazoline-based derivatives was designed and synthesized to explore structure-activity relationships (SAR). Among them, compound W4 showed the most promising profile, exhibiting potent antiproliferative activity against MV4-11 and MOLM-13 cells and strong inhibition of FLT3-ITD (IC = 16.0 nM) and FLT3-D835Y (IC = 20.4 nM), while displaying negligible activity toward c-KIT kinase (IC > 100 μM). Mechanism studies indicated that W4 induced G0/G1 cell cycle arrest and apoptosis, accompanied by a reduction in intracellular reactive oxygen species levels and a loss of mitochondrial membrane potential. Collectively, these results identified W4 as a potent FLT3 inhibitor and provided valuable SAR insights for further scaffold optimization.
Tao J, Xu Y, Chen Z
… +4 more, Liu Y, Zuo X, Yuan T, Yao H
Bioorg Med Chem Lett
· 2026 Jul · PMID 41786053
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Receptor-interacting protein kinase 1 (RIPK1) is a central regulator of necroptosis and a promising therapeutic target for inflammatory and degenerative diseases. Guided by computer-aided drug design (CADD) and structure...Receptor-interacting protein kinase 1 (RIPK1) is a central regulator of necroptosis and a promising therapeutic target for inflammatory and degenerative diseases. Guided by computer-aided drug design (CADD) and structure-based optimizations, we developed a series of phenylbenzothiazole derivatives to enhance RIPK1 inhibition. A total of 36 analogs were efficiently synthesized and fully characterized, incorporating systematic modifications at the R(Degterev et al., 2005, R(Vanlangenakker et al., 2012, and R positions. Their anti-necroptotic activity was evaluated in HT-29 cells under TNF-induced necroptosis. Several compounds (27, 43, 44, and 51) demonstrated significantly improved potency over the lead molecule 18. SAR analysis revealed that CF or OCF at R(Degterev et al., 2005, F or H at R(Vanlangenakker et al., 2012, and 3-oxocyclobutyl or 3-oxocyclopentyl groups at R greatly enhanced activity, indicating more favorable interactions within the RIPK1 binding pocket. These findings identify new phenylbenzothiazole-based inhibitors with promising anti-necroptotic effects and highlight key structural features for future optimization.
Öztaşkın N, Etminan P, Akıncıoğlu A
… +4 more, Çağan A, Demir Y, Göksu S, Gülçin İ
Bioorg Med Chem Lett
· 2026 Jul · PMID 41765051
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Because of the important biological properties of halogenated benzene sulfonamides, here we report the first synthesis of bromophenolic sulfonamides and their human carbonic anhydrase I (hCA I), human carbonic anhydrase...Because of the important biological properties of halogenated benzene sulfonamides, here we report the first synthesis of bromophenolic sulfonamides and their human carbonic anhydrase I (hCA I), human carbonic anhydrase II (hCA II) and acetylcholinesterase (AChE) inhibition. For this purpose, 4-bromo-1,2-dimethoxybenzene was reacted with chlorosulfonic acid fallowed by amination with ammonia, N-alkyl amines and N,N-dialkyl amines to give a series of novel sulfonamides. Subsequent O-demethylation of these sulfonamides using BBr afforded the target bromophenolic benzene sulfonamides. The synthesized bromophenolic sulfonamides were evaluated for their inhibitory effects against both hCA I/II and AChE enzymes. Among these compounds, 2-bromo-4,5-dihydroxy-N-phenylbenzenesulfonamide showed the strongest inhibition against hCA II (Kᵢ = 23.52 nM) and AChE (Kᵢ = 2.29 nM), exhibiting a 12.7 and 21.9-fold better inhibitory effect than the reference inhibitors acetazolamide (Kᵢ = 298.15 nM) and tacrine (Kᵢ = 50.21 nM), respectively. Similarly, N-benzyl-2-bromo-4,5-dihydroxybenzenesulfonamide displayed potent dual inhibition against hCA I (Kᵢ: 53.62 nM) and AChE (Kᵢ: 2.91 nM). In addition, the computational findings obtained from in silico induced fit docking, ADME prediction, and molecular dynamics (MD) simulations further supported and validated the experimental inhibition results.
Kumar P, Singampalli A, Bandela R
… +9 more, Bellapukonda SM, Kodi R, Ghosh S, Korra LN, Dalal A, Devi A, Kalia NP, Nanduri S, Yaddanapudi VM
Bioorg Med Chem Lett
· 2026 Jul · PMID 41759832
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A distinct series of novel pyrazole hydrazide-hydrazone analogues, developed through a structure-activity relationship-driven lead optimization approach, and evaluated for their antitubercular activity. Among the evaluat...A distinct series of novel pyrazole hydrazide-hydrazone analogues, developed through a structure-activity relationship-driven lead optimization approach, and evaluated for their antitubercular activity. Among the evaluated compounds, within the series, compounds 5l and 5m demonstrated notable potency, with MIC values of 0.5 and 1 μg/mL, respectively, along with efficacy against drug-resistant Mycobacterium tuberculosis strains and favorable SI values 23-24. To elucidate the possible mechanism of action, the lead compounds were subjected to molecular docking and 100 ns molecular dynamics simulations, which strongly implicated enoyl-ACP reductase (InhA) as the most probable biological target. Furthermore, in silico ADME analysis revealed favorable pharmacokinetic properties and drug-likeness profiles for the most active derivatives. Collectively, these results highlight the potential of these novel pyrazole hydrazide-hydrazone scaffolds as promising lead candidates for the development of next-generation antitubercular agents, particularly against drug-resistant strains.
Manu J, Singh US, Agboluaje EO
… +4 more, Whittaker MK, Kennedy EJ, Chu CK, Xiong MP
Bioorg Med Chem Lett
· 2026 Jul · PMID 41759831
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Gemcitabine (GEM) is a first line drug to treat pancreatic cancer (PC). However, its long-term efficacy and potency is plagued with reported chemoresistance. To circumvent this issue, the novel GEM analog called troxacit...Gemcitabine (GEM) is a first line drug to treat pancreatic cancer (PC). However, its long-term efficacy and potency is plagued with reported chemoresistance. To circumvent this issue, the novel GEM analog called troxacitabine (TROX) was evaluated alone and in combination with the epigenetic drug 3'-deazaneplanocin (DZNep) against PANC-1 cancer cells. Herein, we report on the synergistic interplay between these two nucleoside analogs in combination (i.e. unprimed combinations) and investigate further the effect of priming PANC-1 cells with DZNep at 8 h versus 24 h followed by TROX (i.e. primed combination). Specific doses at 8 h primed combinations displayed the greatest degree of synergy and were observed between 1.25-5 μM DZNep and 0.5-2 μM TROX in the HSA model, and 1.25-5 μM DZNep and 0.12-0.5 μM TROX in the Loewe model. Data revealed that 8 h primed combinations of DZNep/TROX also reduced self-renewal capability, migratory, and invasive properties of PANC-1 cells more effectively than unprimed (simultaneous) combinations. Proper timed combination of DZNep and TROX may pave the path for an alternative treatment option for GEM-resistant PC.
Jiang F, Zheng C, Wang Y
… +7 more, Hu X, You X, Wang Y, Zhu M, Wang M, Zhang G, Wang J
Bioorg Med Chem Lett
· 2026 Jul · PMID 41747910
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Two series of N-aryl-L-threonine derivatives bearing a triazole fragment are described as LpxC inhibitors targeting Gram-negative pathogens. Most compounds demonstrated stronger antibacterial activities against E. coli (...Two series of N-aryl-L-threonine derivatives bearing a triazole fragment are described as LpxC inhibitors targeting Gram-negative pathogens. Most compounds demonstrated stronger antibacterial activities against E. coli (MICs: ≤0.03-16 μg/mL). Compounds a5, b1 and b2 exhibited pronounced antibacterial activity against Escherichia coli (MICs: ≤0.03-0.5 μg/mL), Klebsiella pneumoniae (MICs: 1-16 μg/mL), and Pseudomonas aeruginosa (MICs: 1-8 μg/mL). Meanwhile, a5 displayed the lowest cytotoxicity toward A549 (IC > 4.032 μg/mL), HepG2 (IC > 4.032 μg/mL), and HEK293 (IC > 0.9112 ± 0.3461 μg/mL) mammalian cells. Against all tested E. coli strains, a5 displayed a therapeutic index of 3.64-67.20. Molecular docking analyses revealed that a5 simultaneously chelated the catalytic zinc ion and established extensive non-covalent interactions within the LpxC active site. This study provides a basis for further research on 1,2,3-triazole compounds.
Bioorg Med Chem Lett
· 2026 Jul · PMID 41747909
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A series of 4-aryl-2-imidazoles containing an ortho-substituted benzyl substituent were designed as a new peptidomimetic scaffold for an Arg-Trp-x-x-Trp motif used by lysis protein E from bacteriophage φX174 to target tr...A series of 4-aryl-2-imidazoles containing an ortho-substituted benzyl substituent were designed as a new peptidomimetic scaffold for an Arg-Trp-x-x-Trp motif used by lysis protein E from bacteriophage φX174 to target translocase MraY on the peptidoglycan biosynthesis pathway. The analogues showed antimicrobial activity against a panel of ESKAPE pathogens, with compound 9c (substituent CF) showing effective antimicrobial activity against antibiotic-resistant Acinetobacter baumannii 19606 (MIC 8 μg/mL) and Staphylococcus aureus MRSA USA300 (MIC 8 μg/mL). The analogues showed 33-47% inhibition of particulate E. coli MraY at 200 μM concentration, with highest enzyme inhibition shown by compound 9b (substituent F, IC 210 μM). Docking against the structure of E. coli MraY revealed a possible binding site in the "elbow" of bent helix 9, close to Phe-288. This work identifies the MraY-protein E interaction site as a possible target for the antimicrobial activity of bromoageliferin, and establishes a new skeleton for design of non-nucleoside MraY inhibitors.
Liao YH, Wang YJ, Wang JQ
… +2 more, Wang HJ, Zhao LM
Bioorg Med Chem Lett
· 2026 Jul · PMID 41747908
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A series of eighteen berberine derivatives were designed and synthesized via molecular hybridization, introducing boronic acid/ester pharmacophores at the C-9 position to improve the selectivity of the natural product ag...A series of eighteen berberine derivatives were designed and synthesized via molecular hybridization, introducing boronic acid/ester pharmacophores at the C-9 position to improve the selectivity of the natural product against breast cancer. The in vitro antiproliferative activities against MDA-MB-468 and MCF-7 cell lines identified several promising leads. Notably, compounds 4c, 5d, 5f, and 8b demonstrated good activity coupled with high selectivity indices over the normal human embryonic kidney (HEK-293) cell line, outperforming berberine and 5-fluorouracil. Computational ADME profiling highlighted 8b and 5f as oral leads and 4c as a BBB-penetrant agent. Molecular docking provided a plausible hypothesis for a proteasome inhibition mechanism for 8b through interaction with the β5 subunit.
Bioorg Med Chem Lett
· 2026 Jul · PMID 41734858
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Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) are potential targets for the development of PD according to current research; nevertheless, reports on dual hIDO1/hTDO inhibitors against...Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) are potential targets for the development of PD according to current research; nevertheless, reports on dual hIDO1/hTDO inhibitors against PD are still lacking. In this study, a series of isoquinoline derivatives were designed, synthesized, and evaluated as novel IDO1/TDO dual inhibitors. Among them, Y-13 showed potent inhibitory activities against both IDO1 (IC = 2.87 ± 0.93 μM) and TDO (IC = 0.08 ± 0.01 μM). The neuroprotective efficiency of Y-13 against PD was explored in vitro and in vivo. It was found that Y-13 could protect BV2 cells from neuroinflammation by inhibiting NO and ROS generation and improve cognitive function, learning ability, and motor performance in a MPTP-induced PD rat model. In general, our study has demonstrated that Y-13 has significant efficacy against PD in vitro and in vivo experiments, which can provide guidance for the development of IDO1/TDO dual inhibitors to treat PD.
Cyriac R, Lee EJ, Kwon Y
… +7 more, Yun MR, Jung ME, Ahn S, Chae CH, Choi G, Cho BC, Lee K
Bioorg Med Chem Lett
· 2026 Jul · PMID 41730394
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Metabolic reprogramming toward glutamine anaplerosis is a well-established vulnerability in tumors harboring co-occurring KRAS and KEAP1 mutations, creating a dependency on glutaminase (GLS)-mediated glutaminolysis for s...Metabolic reprogramming toward glutamine anaplerosis is a well-established vulnerability in tumors harboring co-occurring KRAS and KEAP1 mutations, creating a dependency on glutaminase (GLS)-mediated glutaminolysis for survival and growth. Although allosteric GLS inhibitors such as BPTES (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide) and later-generation analogs such as CB-839 (Telaglenastat) have pharmacologically validated this target, their clinical utility has been constrained by suboptimal drug-like properties, including poor solubility and bioavailability. To overcome these limitations, we developed TRG-192, a novel symmetric amidothiadiazole derivative engineered with a distinct chemical scaffold to enhance physicochemical and pharmacokinetic profiles. In vitro characterization revealed that TRG-192 is a potent GLS inhibitor (IC₅₀ = 68 nM). This biochemical potency translated to a functional effect in a cellular model of glutamine dependence, as evidenced by a significant depletion of intracellular glutamate pools in LDK378-resistant (LR) cells. Furthermore, TRG-192 demonstrated a favorable preclinical safety profile in initial toxicological assessments. Collectively, these data-encompassing potent target engagement, functional on-target activity, and preliminary safety-provide a compelling rationale for the advancement of TRG-192 into in vivo efficacy studies.
Ambala S, Bhookya S, Pochampally S
… +2 more, Pochampally J, Balabadra S
Bioorg Med Chem Lett
· 2026 Jul · PMID 41720410
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A set of novel 1,2,4-oxadiazol based piperidin-1-yl-methanone analogues (5a-k) was synthesized from 3-phenyl-5-(4-(piperidin-4-yl)phenyl)-1,2,4-oxadiazole (3) via a sequential hydrolysis, cyclization and the Schotten-Bau...A set of novel 1,2,4-oxadiazol based piperidin-1-yl-methanone analogues (5a-k) was synthesized from 3-phenyl-5-(4-(piperidin-4-yl)phenyl)-1,2,4-oxadiazole (3) via a sequential hydrolysis, cyclization and the Schotten-Baumann reaction. The structures of synthesized compounds were characterized using H NMR, C NMR and mass spectrometry data. Moreover, all compounds were evaluated for their preliminary antimicrobial activity against Gram-negative, Gram-positive bacterial, as well as fungal pathogens, employing the disk diffusion method. Most of the evaluated compounds displayed exceptional antimicrobial activity, when compared with standard Ampicillin, Griseofulvin. Notably, compounds 5b, 5e, 5i, 5j and 5k exhibited significant anti-bacterial activity, with zone of inhibition of 20-25 mm at 50 μg/ml and MIC values ranging from 1.6-2.2 μg/mL. The antifungal activity revealed MIC values in the range of 1.7-1.9 μg/mL. Molecular docking studies were conducted against penicillin-binding protein (PBP, PDB ID: 3TTZ), a key enzyme involved in bacterial cell wall biosynthesis. The synthesized compounds exhibited favorable binding interactions within the active site of PBP through H-bonds and hydrophobic interactions, supported by stable binding energies, with crucial residues. These results suggest that the developed 1,2,4-oxadiazol based piperidin-1-yl-methanone analogues favorable stability, have potential as effective antibacterial agents against targeting PBP inhibition.
Liu S, Dang B, Kang Z
… +8 more, Wei R, Yang Z, Guo X, Shao F, Li Z, Xing L, Hu J, Chen X
Bioorg Med Chem Lett
· 2026 Jul · PMID 41713755
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Recently, histone deacetylase 6 (HDAC6) has attracted considerable attention for its potential in treating neurodegenerative disorders. In this paper, a series of tetrahydroisoquinoline derivatives were designed and synt...Recently, histone deacetylase 6 (HDAC6) has attracted considerable attention for its potential in treating neurodegenerative disorders. In this paper, a series of tetrahydroisoquinoline derivatives were designed and synthesized as selective HDAC6 inhibitors. 4-((7-chloro-3, 4-dihydroisoquinolin-2(1H)-yl)methyl)-3-fluoro-N-hydroxybenzamide (8g), the most promising compound, potently inhibited HDAC6 (IC = 7.0 nM) and exhibited >2000 ~ fold selectivity over HDAC1. Molecular simulation indicated its molecular basis of HDAC6 inhibition. In vitro, 8g showed no significant toxicity on rat dopaminergic pheochromocytoma PC-12 cells. Furthermore, we demonstrated that 8g induced neurite outgrowth and showed good neuroprotective activity in PC-12 cells. Our research provided a new promising structure for the development of HDAC6is against Alzheimer's disease.
Bioorg Med Chem Lett
· 2026 Jul · PMID 41702465
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Highly pathogenic avian influenza virus (HPAIV) is an enveloped virus currently spreading among birds around the world, and infections in humans have been reported. Common disinfectants such as ethanol and chlorine are s...Highly pathogenic avian influenza virus (HPAIV) is an enveloped virus currently spreading among birds around the world, and infections in humans have been reported. Common disinfectants such as ethanol and chlorine are somewhat effective, but the development of more effective disinfectants to prevent infection is urgently needed. As a result of a series of studies focusing on cationic antibacterial agents, DEA-171 has been developed as a safe and effective anti-enveloped virus by adding sulfobetaine to a specific quaternary ammonium cation. This solution inactivated approximately 99.0% of H5 HPAIV in 30 min.
Yang W, Chen K, Wu J
… +4 more, Huang X, Wei C, Xu Y, Chen H
Bioorg Med Chem Lett
· 2026 Jul · PMID 41702464
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A one-pot approach was developed for the direct synthesis of novel benzooxepino-fused tetrahydroquinoline-fused iminosugars via an intramolecular aza-Diels-Alder reaction mediated by an aryl iminium ion. The obtained mul...A one-pot approach was developed for the direct synthesis of novel benzooxepino-fused tetrahydroquinoline-fused iminosugars via an intramolecular aza-Diels-Alder reaction mediated by an aryl iminium ion. The obtained multicyclic fused iminosugars were evaluated for their inhibitory activity against α- and β-glucosidases. The results showed that the iminosugars derived from l-ribose demonstrated significantly inhibitive activity against α-glucosidase, with IC values ranging from 2.77 μM to 6.12 μM. Kinetic analyses based on Lineweaver-Burk plots (1/V versus 1/[S]) indicated that compounds 3ba and 3bd act as rare uncompetitive inhibitors against α-glucosidase, with calculated Ki values of 10.50 ± 0.35 μM and 9.28 ± 0.31 μM, respectively.
Xu C, Wang R, Liu F
… +7 more, Huang J, Deng Y, Li J, Wang Y, Dehaen W, Fang Y, Huai Q
Bioorg Med Chem Lett
· 2026 Jul · PMID 41702463
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To address the systemic toxicity of podophyllotoxin (PPT), two series of mitochondria-targeted PPT derivatives were designed and synthesized by conjugating PPT with delocalized lipophilic cations (DLCs) TPP and F16 via a...To address the systemic toxicity of podophyllotoxin (PPT), two series of mitochondria-targeted PPT derivatives were designed and synthesized by conjugating PPT with delocalized lipophilic cations (DLCs) TPP and F16 via alkyl linkers. Biological evaluation revealed that the F16-conjugated compound 6d exhibited the most potent antiproliferative activity against HepG2 cells with an IC value of 0.66 μM, which was significantly superior to the positive control etoposide with an IC of 10.82 μM. Additionally, 6d demonstrated improved selectivity toward normal hepatocytes (QSG-7701) with a selectivity index of 2.29. Colocalization studies confirmed that 6d specifically accumulates in mitochondria, with a Pearson's correlation coefficient of 0.90. Flow cytometry analysis further demonstrated that 6d induces apoptosis in a concentration-dependent manner. These findings highlight compound 6d as a promising mitochondria-targeted lead agent for liver cancer therapy.
Wu JH, Xing YH, Wang XH
… +4 more, Gao WJ, Liu XY, Yue JM, Yu JH
Bioorg Med Chem Lett
· 2026 Jul · PMID 41692313
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This study reports the rational design, synthesis, and biological evaluation of imidazole-based apo-IDO1 inhibitors. Based on the established three-component pharmacophore model, we innovatively introduced an imidazole r...This study reports the rational design, synthesis, and biological evaluation of imidazole-based apo-IDO1 inhibitors. Based on the established three-component pharmacophore model, we innovatively introduced an imidazole ring as the central linker to bridge Fragments A and B. Systematic structure-activity relationship (SAR) studies afforded the most potent compound YC-16, with an IC value of 0.18 ± 0.01 μM and no significant cytotoxicity. YC-16 exhibits comparable potency across diverse tissue-derived cell lines, demonstrating broad tissue selectivity. Mechanistic studies confirmed that YC-16 does not alter IDO1 expression but acts as an apo-IDO1 inhibitor through two complementary mechanisms: slow competitive displacement of heme from mature holo-IDO1 and rapid binding to the heme-binding site of immature apo-IDO1. These findings establish YC-16 as a promising pan-tissue apo-IDO1 inhibitor and provide a clear foundation for further structural optimization.
Xu N, Zhao Y, Liu J
… +8 more, Mao Z, Feng H, Zhang T, Yu J, Yuan Y, Chen X, Qiu T, Ma L
Bioorg Med Chem Lett
· 2026 Jun · PMID 41692312
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Point mutations and fusions in the Rearranged during Transfection (RET) proto-oncogene are established drivers in diverse malignancies. Although selective RET inhibitors such as selpercatinib and pralsetinib have been cl...Point mutations and fusions in the Rearranged during Transfection (RET) proto-oncogene are established drivers in diverse malignancies. Although selective RET inhibitors such as selpercatinib and pralsetinib have been clinically approved, the emergence of resistance mutations limits their durable efficacy, underscoring the need for novel therapeutic modalities. Targeted protein degradation (TPD), which harnesses the endogenous ubiquitin-proteasome system to induce protein degradation, provides a promising strategy to overcome resistance to traditional small-molecule inhibitors. In this study, we systematically evaluated two distinct TPD approaches, proteolysis-targeting chimeras (PROTACs) and hydrophobic tag tethering degraders (HyTTDs). We report the design and synthesis of the first RET-targeting HyTTD, compound B2, which achieves 91.4% degradation of CCDC6-RET fusion protein in TPC-1 cells at 10 μM within 48 h. These results not only validate hydrophobic tag tethering as a feasible strategy for RET degradation but also propose a new therapeutic direction for RET-driven cancers.
Niu Y, Wang W, Xie Y
… +5 more, Zhang L, Liu X, Gong L, Chen J, Zuo Z
Bioorg Med Chem Lett
· 2026 Jun · PMID 41692311
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Peroxisome proliferator-activated receptor α (PPARα) represents a critical therapeutic target for dyslipidemia. To discover novel scaffold agonists, we used Pemafibrate as a template to construct a focused chemical libra...Peroxisome proliferator-activated receptor α (PPARα) represents a critical therapeutic target for dyslipidemia. To discover novel scaffold agonists, we used Pemafibrate as a template to construct a focused chemical library with the infiniSee software. An integrated virtual screening approach, including molecular docking, MM-GBSA binding free energy calculations, ADMET profiling, and visual inspection, was applied to identify a hit compound. Subsequent structural optimization led to the synthesis of 40 derivatives. Among the tested compounds, XYQ3-B11 was identified as the most potent PPARα activator. In the luciferase reporter assay, XYQ3-B11 exhibited an EC value of 8.33 μM, better than the reference agonist WY14643 (EC = 16.10 μM). Notably, XYQ3-B11 possesses a distinctive hybrid architecture, comprising a central pyridine ring, a 2-fluorobenzoate moiety, and an indole-derived side chain. These findings highlight XYQ3-B11 as a promising novel chemotype for the start of development of PPARα agonists.
Yang W, Jia X, Yang W
… +5 more, Liao Q, Li Y, Shen X, Zhang X, Wang C
Bioorg Med Chem Lett
· 2026 Jun · PMID 41692310
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Mas-related G protein-coupled receptor X2 (MRGPRX2) is a novel G protein-coupled receptor (GPCR) that has been identified as a potential therapeutic target for pseudo allergic diseases. The development of novel MRGPRX2 a...Mas-related G protein-coupled receptor X2 (MRGPRX2) is a novel G protein-coupled receptor (GPCR) that has been identified as a potential therapeutic target for pseudo allergic diseases. The development of novel MRGPRX2 antagonists possesses tremendous therapeutic and social implications. Recent efforts have been invested in finding specific MRGPRX2 inhibitors for potential therapeutic approaches, although none has been approved for clinical use to date. We previously identified Imperatorin (the furanocoumarin compound) as a lead molecule for MRGPRX2 antagonist. In this study, we investigated the anti-pseudo-allergic effect of the fourteen synthesized furanocoumarin derivatives, as well as the relationship between their activity and MRGPRX2 receptor. In vitro and in vivo experimental results showed that compounds XAT-13 and XAT-14 can suppress compound 48/80-induced Mast cells degranulation in a good dose-dependent manner. Molecular docking implied that XAT-13 and XAT 14 may shared the same binding sites with C48/80. Our study revealed that the novel small molecules (XAT-13 and XAT-14) as early-stage lead compounds, which can be further optimized to obtain therapeutic drug candidates to address MRGPRX2 mediated allergic reactions and other inflammatory diseases.
Kamata Y, Saito N, Fujihira H
… +3 more, Suzuki T, Hirose M, Totani K
Bioorg Med Chem Lett
· 2026 Jun · PMID 41687896
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Endoplasmic reticulum-associated degradation facilitates the elimination of misfolded glycoproteins through a sequential process involving deglycosylation by cytosolic PNGase, followed by the removal of GlcNAc residues b...Endoplasmic reticulum-associated degradation facilitates the elimination of misfolded glycoproteins through a sequential process involving deglycosylation by cytosolic PNGase, followed by the removal of GlcNAc residues by ENGase. Genetic mutations in NGLY1, the mammalian ortholog of PNGase, have been implicated in the rare congenital disorder known as NGLY1 deficiency. The pathology of this disorder is suggested to be partially due to N-GlcNAc proteins generated by ENGase activity. Consequently, the development of tools to detect PNGase and ENGase activities is crucial for advancing our understanding of related diseases. In established assay systems for PNGase activity, glycan probes incorporating cyclic peptides with protease resistance have been used. However, the cyclic peptide motif is associated with synthetic complexity owing to multiple reaction steps. In this study, we developed glycopeptide probes, ManGlcNAc-Asn(Fmoc)-Leu-Leu-R (R = Bn or OH), specifically designed to monitor PNGase and ENGase activities. The ManGlcNAc moiety, a high-mannose-type oligosaccharide that is efficiently recognized by ENGase, was selected due to its ready availability from hen egg yolk. Additionally, the Asn-Leu-Leu sequence, which is easily synthesized and exhibits high affinity for PNGase, was chosen for its anticipated protease resistance, as it is a common motif in protease inhibitors. Both glycopeptide probes successfully detected the activities of purified PNGase and ENGase. Notably, ManGlcNAc-Asn(Fmoc)-Leu-Leu-OH enabled accurate activity detection even in crude rat liver lysates without peptide degradation. Furthermore, in wild-type and Ngly1 (Pngase)- or Engase-knockout cytosol from MEF cells, the probe demonstrated practical utility as a molecular tool in terms of degradation resistance and monitoring of enzymatic activities.