Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Discovery of small molecule CHI3L1 inhibitors by SPR-based high-throughput screening","authors":"Longfei Zhang,&nbsp;Hossam Hammouda Nada Hammouda,&nbsp;Moustafa T. Gabr","doi":"10.1016/j.bmcl.2025.130460","DOIUrl":"10.1016/j.bmcl.2025.130460","url":null,"abstract":"<div><div>Chitinase-3-like 1 (CHI3L1) is a secreted glycoprotein implicated in carcinogenesis and tumor immune evasion. Elevated CHI3L1 expression is frequently detected in cancer patients, highlighting it as a promising therapeutic target. To overcome the limited availability of small molecule CHI3L1 inhibitors, we established a surface plasmon resonance (SPR)–based high-throughput screening platform and applied it to a focused chemical library of small molecules. Primary screening identified seven hits, with compounds <strong>1–4</strong> and <strong>1–7</strong> validated as CHI3L1 binders (<em>Kd</em> = 10.4 ± 1.0 μM and 7.40 ± 0.78 μM, respectively). Both compounds disrupted the CHI3L1–galectin-3 interaction in AlphaLISA assays and engaged the CHI3L1 binding pocket in docking and molecular dynamics (MD) simulations. Importantly, functional evaluation in a multicellular 3D glioblastoma (GBM) spheroid model demonstrated that compound <strong>1–7</strong> potently reduced spheroid viability and inhibited STAT3 phosphorylation, outperforming both compound <strong>1–4</strong> and the known CHI3L1–STAT3 disruptor hygromycin B (HB). These findings validate SPR as a robust primary screening platform for CHI3L1 and demonstrate that the identified small molecule binders exert functional activity in a physiologically relevant multicellular GBM spheroid model.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130460"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of affinity-optimized peptide binders of a viral protease for chemical genetic applications","authors":"Fernando Banales-Mejia ,&nbsp;Emily M. Dieter ,&nbsp;Kyler J. Radmall ,&nbsp;Glenna W. Foight ,&nbsp;Douglas M. Fowler ,&nbsp;Dustin J. Maly","doi":"10.1016/j.bmcl.2025.130463","DOIUrl":"10.1016/j.bmcl.2025.130463","url":null,"abstract":"<div><div>Chemically-controlled genetic tools are useful for studying biological systems due to their ability to dose-dependently and temporally modulate intracellular function. Chemically-disrupted proximity (CDP) systems, which involve the pre-localization of two interacting protein components that can be disrupted with a small molecule, are complementary to more commonly used chemically-inducible dimerization (CID) systems. However, fewer CDP systems have been developed, and the genetically-encoded protein components have not been as optimized for intracellular applications. Here, we describe a transcriptional activation reporter assay for screening the intracellular interaction between the 21-amino acid peptide ANR and HCVp NS3a, which are the genetically-encoded components of a CDP system that utilizes clinically-approved antiviral drugs. We used this assay to screen a library of single amino acid substitution ANR variants and identified several that increase the intracellular interaction between ANR and NS3a. By combining affinity-optimized single substitutions, we achieved improved transcriptional activation and engineered an autoinhibited signaling switch with low basal activity. Together, our study describes a functional assay for screening genetically-encoded CDP components and a more optimized version of ANR for intracellular applications.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130463"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the combinatorial anticancer effects of imidazolium-based ionic liquids and lysosomotropic detergents with cisplatin and doxorubicin","authors":"Anastasiia Gryniukova ,&nbsp;Sergiy Rogalsky ,&nbsp;Petro Borysko ,&nbsp;Diana Hodyna ,&nbsp;Vasyl Kovalishyn ,&nbsp;Larysa Metelytsia","doi":"10.1016/j.bmcl.2025.130474","DOIUrl":"10.1016/j.bmcl.2025.130474","url":null,"abstract":"<div><div>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 <em>in vitro</em> 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 (IMC₁₂C₁-Cl), 1-dodecyloxycarbonylmethyl-3-methylimidazolium chloride (IMC₁CH₂COOC₁₂-Cl), and, to a lesser extent, lysosomotropic detergent 1-dodecylimidazole (IMC₁₂) consistently stand out as the most promising across all cell lines. IMC₁₂C₁-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. IMC₁CH₂COOC₁₂-Cl showed high DRI and synergism in MCF7 cells and moderate activity in SK-N-DZ cells. IMC₁₂C₁-Cl and IMC₁CH₂COOC₁₂-Cl appear to be promising candidates for the development and evaluation of their combinatorial anticancer effects.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130474"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Worm-like gold nanocrystals fabricated using a self-assembling peptide and inducing cell death upon exposure to near infrared light","authors":"Soo-Ang Ahn ,&nbsp;Kazutoshi Ishida ,&nbsp;Ryuki Watanabe ,&nbsp;Takahito Imai ,&nbsp;Masayuki Yamasaki ,&nbsp;Kin-ya Tomizaki","doi":"10.1016/j.bmcl.2025.130472","DOIUrl":"10.1016/j.bmcl.2025.130472","url":null,"abstract":"<div><div>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/cm² 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.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130472"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Late-stage functionalization of Cycloastragenol and anti-inflammatory study","authors":"Yong Wang ,&nbsp;Yingchuan Que ,&nbsp;Yi Gu ,&nbsp;Jia Xia ,&nbsp;Yi Dong ,&nbsp;Lumin Tang ,&nbsp;Shan Mou ,&nbsp;Gang Chen","doi":"10.1016/j.bmcl.2025.130442","DOIUrl":"10.1016/j.bmcl.2025.130442","url":null,"abstract":"<div><div>Cycloastragenol (CAG), a bioactive compound from Huangqi, exhibits anti-inflammatory properties but has poor water solubility. This study enhanced CAG's solubility via C3-position modifications, synthesizing phosphorylated, sulfonated, and glycosylated derivatives with improved solubility. The phosphorylated derivative (<strong>11a</strong>) excelled in suppressing nitric oxide (NO) production in LPS-induced RAW264.7 macrophages. Further investigation revealed that both CAG and <strong>11a</strong> effectively reduced levels of pro-inflammatory cytokines IL-6 and TNF-α, suggesting their anti-inflammatory effects are mediated through these pathways. Our findings indicate that chemical modifications can successfully enhance the solubility of CAG without compromising its bioactivity, with derivative <strong>11a</strong> emerging as a particularly promising candidate for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130442"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An efficient approach to flavan-4-ols via radiolysis and their inhibitory activity against cytokine production","authors":"Gyeong Han Jeong ,&nbsp;Ha-Yeon Song ,&nbsp;Hanui Lee ,&nbsp;Byung Yeoup Chung ,&nbsp;Kyung-Bon Lee ,&nbsp;Hyoung-Woo Bai","doi":"10.1016/j.bmcl.2025.130464","DOIUrl":"10.1016/j.bmcl.2025.130464","url":null,"abstract":"<div><div>Facile structural modification of naringin (<strong>1</strong>) induced by γ-irradiation produced five novel hydroxymethylated flavan-4-ols, namely, narinflavans A (<strong>2</strong>), B (<strong>3</strong>), C (<strong>4</strong>), D (<strong>5</strong>), and E (<strong>6</strong>). The structures of the newly synthesized flavan derivatives were determined through comprehensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses, whereas their absolute configurations were confirmed by electronic circular dichroism (ECD) spectroscopy. The new unusual flavan derivatives <strong>4</strong> and <strong>5</strong> containing a hydroxymethyl, instead of a ketone moiety, exhibited significantly modulated inhibitory effects on cytokine production than the parent compound. These results highlight γ-irradiation as an efficient one-step approach to generate structurally novel flavan-4-ols with biological functions.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130464"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting telomerase for lung cancer: design and synthesis of acridine hybrids with in vitro and in vivo evaluation","authors":"Keerti Vishwakarma,&nbsp;Rajdeep Dey,&nbsp;Hardik Bhatt","doi":"10.1016/j.bmcl.2025.130465","DOIUrl":"10.1016/j.bmcl.2025.130465","url":null,"abstract":"<div><div>Lung cancer remains the leading cause of cancer-related deaths worldwide, emphasizing the need for effective targeted therapeutics. Telomerase, which is aberrantly activated in most lung tumors, is an attractive molecular target; however, the clinical translation of its inhibitors has been limited. In this study, we employed a rational design approach that integrated pharmacophore modeling, virtual screening, QSAR, and molecular docking to develop acridine–thiadiazole hybrids as potential telomerase inhibitors. Guided by pharmacophore-based virtual screening and 3D-QSAR studies, 32 derivatives were synthesized through an optimized route for synthesis and evaluated for anticancer activity. Several compounds displayed potent sub-micromolar cytotoxicity against A549 lung cancer cells with minimal toxicity toward Vero cells. Among them, compound <strong>28</strong> emerged as the most potent, exhibiting nanomolar activity and strong telomerase inhibition, while compounds <strong>21</strong>, <strong>29</strong>, and <strong>39</strong> also demonstrated significant efficacy. Mechanistic studies confirmed apoptosis induction, inhibition of clonogenic survival, and telomerase suppression. <em>In vivo</em> evaluation in a benzo[<em>a</em>]pyrene-induced lung cancer model further validated the therapeutic potential of these hybrids, showing reduced tumor burden, restoration of antioxidant balance, and preservation of lung architecture. Collectively, these findings highlight acridine–thiadiazole hybrids, particularly compound <strong>28</strong>, as promising, selective telomerase inhibitors for lung cancer therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130465"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysine-reactive tag system for cell-surface protein labeling via N-acyl-N-alkyl sulfonamide chemistry","authors":"Vikram Thimaradka,&nbsp;Tomonori Tamura,&nbsp;Itaru Hamachi","doi":"10.1016/j.bmcl.2025.130470","DOIUrl":"10.1016/j.bmcl.2025.130470","url":null,"abstract":"<div><div>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 (BisNi²⁺-NTA) complex probe containing a lysine-reactive <em>N</em>-acyl-<em>N</em>-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.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130470"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision engineering of adalimumab fab variants enhances TNF-α neutralization and structural stability","authors":"Abida Khan ,&nbsp;Abdullah R. Alzahrani ,&nbsp;Zia Ur Rehman ,&nbsp;Syeda Huma H. Zaidi ,&nbsp;Abdul Hai ,&nbsp;Maha M. Al-Bazi ,&nbsp;Abeer A. Banjabi ,&nbsp;Mohd Imran","doi":"10.1016/j.bmcl.2025.130475","DOIUrl":"10.1016/j.bmcl.2025.130475","url":null,"abstract":"<div><div>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 <em>in-silico</em> 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 <em>E. coli</em> 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<span><span>²</span></span>). 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_total (−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.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130475"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coumarin–benzimidazole hybrids: Design, synthesis and identification of potential anticancer agents","authors":"C.G. Arya ,&nbsp;Neethu Mariam Thomas ,&nbsp;Munugala Chandrakanth ,&nbsp;Anoop Kallingal ,&nbsp;P.G. Amrutha ,&nbsp;M.S. Sivapriya ,&nbsp;Ramesh Gondru ,&nbsp;Janardhan Banothu","doi":"10.1016/j.bmcl.2025.130444","DOIUrl":"10.1016/j.bmcl.2025.130444","url":null,"abstract":"<div><div>A series of coumarin–benzimidazole conjugates (<strong>6a–p</strong>) was designed and synthesized <em>via</em> a polyphosphoric acid (PPA)-mediated condensation of <em>o</em>-phenylenediamine derivatives with coumarin-3-carboxylic acids. The <em>in vitro</em> anticancer activity of all conjugates was evaluated against lung (A549) and breast (MCF7) cancer cell lines. Except for hybrids <strong>6l</strong> (A549) and <strong>6c</strong> (MCF7), all compounds exhibited notable cytotoxicity toward both cell lines, with IC₅₀ values ranging from 0.85 ± 0.07 to 48.01 ± 0.45 μM. Among them, the unsubstituted derivative <strong>6b</strong> emerged as the most potent compound, showing IC₅₀ values of 0.85 ± 0.07 μM (A549) and 1.90 ± 0.08 μM (MCF7). Compounds <strong>6a</strong>, <strong>6c</strong>, and <strong>6g</strong> also demonstrated strong activity against A549 cells, with IC₅₀ values of 1.86 ± 0.19 μM, 1.05 ± 0.09 μM, and 2.23 ± 0.13 μM, respectively. Furthermore, the potent conjugates <strong>6b</strong> and <strong>6g</strong> were found to be non-toxic toward Vero cells (LD₅₀ &gt; 100 μM), indicating selective cytotoxicity toward cancer cells. <em>In silico</em> molecular docking studies suggested that the activity of compound <strong>6b</strong> against both cell lines may result from inhibition of sphingosine kinase 1 (SK1), whereas the potency of <strong>6g</strong> against A549 cells could be attributed to cyclin-dependent kinase 2 (CDK2) inhibition. These computational predictions warrant further validation through target-specific biological assays. ADMET analysis further revealed that conjugate <strong>6b</strong> possesses favorable pharmacokinetic properties, supporting its potential as a promising lead for future anticancer drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130444"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}