Chemico-Biological Interactions最新文献

{"title":"Structure optimization, synthesis and bioactivity evaluation of novel BCR-ABL tyrosine kinase inhibitor targeting T315I mutation","authors":"Shuo Wang ,&nbsp;Jingjing Chen ,&nbsp;Rui Hou ,&nbsp;Yijing Xiong ,&nbsp;Huaihuai Shi ,&nbsp;Zhesheng Chen ,&nbsp;Jiazhong Li ,&nbsp;Xin Wang","doi":"10.1016/j.cbi.2024.111248","DOIUrl":"10.1016/j.cbi.2024.111248","url":null,"abstract":"<div><div>Chronic Myeloid Leukemia (CML) is a malignant hematologic tumor caused by BCR-ABL fusion protein that binds with ATP to exert tyrosinase activity and persistently activates downstream phosphorylation pathways. The tyrosine kinase inhibitors (TKIs) represented by Imatinib are the key clinical therapy to the CML. While the mutations on the target lead to the serious drug resistance problems, especially the T315I mutation remains an unresolved challenge, and the cardiotoxicity has limited the clinical application of the third generation TKI Ponatinib despite its favorable efficacy against the T315I mutation. Even though, structural optimization of Ponatinib remains a potential strategy to overcome the resistance imposed by the mutation. Herein, we present a series of novel BCR-ABL/T315I tyrosine kinase inhibitors obtained by virtual screening using ZINC21710815, a BCR-ABL/T315I inhibitor reported earlier by our team, as a lead compound, and structural optimization of lead compounds against the T315I mutation, as well as screening of two novel compounds by activity evaluation and mechanistic studies, W4 and W8. W4 and W8 have better cell death-inducing effects and special selectivity against BaF3/T315I, which are worthy of further in-depth study to obtain more desirable anti-CML drugs as lead compounds.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111248"},"PeriodicalIF":4.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CGS-21680 defers cisplatin-induced AKI-CKD transition in C57/BL6 mice","authors":"Menna A. Elbrolosy,&nbsp;Manar G. Helal,&nbsp;Mirhan N. Makled","doi":"10.1016/j.cbi.2024.111255","DOIUrl":"10.1016/j.cbi.2024.111255","url":null,"abstract":"<div><div>Acute kidney injury (AKI), with a high mortality and morbidity, is known as a risk factor for developing progressive chronic kidney disease (CKD). Targeting transition of AKI to CKD displays an excellent therapeutic potential. This study aims at investigating the role of CGS-21680, selective A2AR agonist, in deferring <em>Cis</em>-induced AKI-CKD transition. The AKI-CKD transition model was induced in C57/BL6 mice by repeated low doses of Cis (2.5 mg/kg i.p for 5 consecutive days in two cycles with a recovery phase of 16 days between two cycles). CGS-21680 was administered daily for 6 weeks (0.1 mg/kg, i.p). Urine, blood, and kidney were collected at three different time points to track the disease progression. CGS-21680 administration preserved kidney function and attenuated tubular damage as evidenced by hematoxylin-eosin (H&amp;E) histopathology. CGS-21680 significantly restored oxidative status as reflected by reduced malondialdehyde (MDA) content and increased total antioxidant capacity (TAC). CGS-21680 showed anti-inflammatory effect as indicated by decreased TNF-α and iNOS. Additionally, CGS-21680 ameliorated endothelial dysfunction and enhanced renal vasodilation as evidenced by upregulation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) expression and down regulation of endothelin-1 (ET-1) and its receptor endothelin-A (ET-A) receptor expression. CGS-21680 also attenuated renal fibrosis as reflected by the reduction of percentage of fibrosis in Masson's trichome-stained renal sections and down regulation of transforming growth factor beta1 (TGF-β1) protein expression in IHC-stained renal sections. In conclusion, CGS-21680 could defer <em>Cis</em>-induced AKI-CKD transition via its vasodilatory, antioxidant, anti-inflammatory, and anti-fibrotic effects.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111255"},"PeriodicalIF":4.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the anticancer potential of Cytotoxin 10 from Naja kaouthia venom: Mechanistic insights from breast and lung cancer cell lines","authors":"Mandira Basumatary,&nbsp;Amit Talukdar,&nbsp;Manoj Sharma,&nbsp;Anupam Dutta,&nbsp;Rupak Mukhopadhyay,&nbsp;Robin Doley","doi":"10.1016/j.cbi.2024.111254","DOIUrl":"10.1016/j.cbi.2024.111254","url":null,"abstract":"<div><div>Breast and lung cancers are the leading causes of cancer-related deaths in the world. Although considerable progress has been made in the field of cancer therapy, quest to discover potent, safe and cost-effective alternatives especially from natural sources is being pursued. Snake venom, which is a treasure trove of various peptides and proteins including natural toxins that specifically target tissues and receptors in the envenomated victims. Many such proteins are being explored for their therapeutic potential against various diseases including cancers. Here, we report the mechanism of cytotoxic activity of crude venom and a purified protein, Cytotoxin from the monocled cobra (<em>Naja kaouthia</em>), an elapid snake with neurotoxic venom prominently found in the North-East India. The crude venom showed significant cytotoxicity against breast (MCF-7and MDA-MB-231) and lung (A549, NCI–H522) cancer cell lines. Bioassay-guided fractionation using RP-HPLC showed highest cytotoxic activity in peak P9. Liquid chromatography-tandem mass spectrometry (ESI-LC-MS/MS) analysis was employed and the fraction is identified as Cytotoxin 10 which showed comparable cytotoxicity against the experimental cell lines. Cytotoxin 10 also exhibited apoptosis in MCF-7 and A549 cell lines using AO/EtBr and flow cytometry analysis. Expressions of apoptosis related proteins e.g. Bax, Bcl-2, Caspase-7 and PARP were also studied following Cytotoxin 10 treatment in both cell lines. Molecular docking experiments performed to investigate the interactions between Cytotoxin 10 and the apoptotic proteins revealed favourable binding scores compared to their corresponding inhibitors. Interestingly, Cytotoxin 10 inhibited migration and adhesion in a time and dose-dependent manner in both MCF-7 and A549 cells. This is the first report elucidating the mechanism of cytotoxic activity of Cytotoxin 10 purified from <em>Naja kaouthia</em> venom of North-East India origin and could pave the way for development of potential therapeutic strategies against breast and lung cancer.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111254"},"PeriodicalIF":4.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGCG inhibits migration, invasion and epithelial-mesenchymal transition of renal cell carcinoma by activating TFEB-mediated autophagy","authors":"Bo Liu ,&nbsp;Lei Luo ,&nbsp;Bixin Yu ,&nbsp;Taotao Que ,&nbsp;Yujiao Zhang","doi":"10.1016/j.cbi.2024.111250","DOIUrl":"10.1016/j.cbi.2024.111250","url":null,"abstract":"<div><h3>Background</h3><div>The incidence of renal cell carcinoma (RCC) is already in the top ten of all types of cancers, with more than 4 %. Epigallocatechin gallate (EGCG), a polyphenolic compound extracted from green tea, has been shown to be effective in the treatment of various tumors. However, limited studies have demonstrated the effect of EGCG on RCC and its underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>After exposure to gradient concentration (0,5,10,20,40,60,80,100 μM) of EGCG, the cell viability of RCC cells was determined by MTT assay. The migration and invasion abilities of RCC cells were investigated by wound healing and transwell assays. The expression levels of proteins involved in the epithelial-mesenchymal transition (EMT) and autophagy were explored by Western blotting assays. The formation of autophagosome was detected by electron microscope and LC3 puncta assays. Nude mouse xenograft model was used as the model system in vivo.</div></div><div><h3>Results</h3><div>In the present study, EGCG significantly inhibited the migration, invasion and EMT of RCC cells in a concentrated manner. Further exploration of its mechanism indicated that autophagy is involved in EGCG-mediated metastasis inhibition and EMT inhibition of RCC cells. In addition, EGCG could significantly up-regulate the transcription factor EB (TFEB) and promotes its nuclear localization. The incorporation of TFEB into the nucleus enhanced the transcriptional levels of molecules associated with autophagy. TFEB knockdown inhibited EGCG-mediated autophagy activation, metastasis and EMT inhibition in RCC cells.</div></div><div><h3>Conclusions</h3><div>In conclusion, these findings demonstrate for the first time that EGCG inhibits migration, invasion, and EMT of RCC by activating TFEB-mediated autophagy. Therefore, the combination of EGCG and TFFB activators or EMT inhibitors is expected to be a promising therapeutic strategy for RCC.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111250"},"PeriodicalIF":4.7,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142309365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of human and rat placental 3β-hydroxysteroid dehydrogenases by bisphenol A analogues depends on their hydrophobicity: In silico docking analysis","authors":"Shaowei Wang ,&nbsp;Han Lu ,&nbsp;Yingna Zhai ,&nbsp;Yunbing Tang ,&nbsp;Ming Su ,&nbsp;Huitao Li ,&nbsp;Yiyan Wang ,&nbsp;Yi Liu ,&nbsp;Ren-shan Ge","doi":"10.1016/j.cbi.2024.111251","DOIUrl":"10.1016/j.cbi.2024.111251","url":null,"abstract":"<div><div>Bisphenol A (BPA) and its analogues are widely used industrial chemicals. Placental 3β-hydroxysteroid dehydrogenases (3β-HSDs) catalyse the conversion of pregnenolone to progesterone. However, the potency of BPA analogues in inhibiting 3β-HSDs activity remains unclear. We investigated the inhibitory effect of 10 BPA analogues on 3β-HSDs activity using an <em>in vitro</em> assay and performed the structure-activity relationship and in silico docking analysis. BPH was the most potent inhibitor of human 3β-HSD1, with an IC₅₀ value of 0.95 μM. BPFL, BPG, DABPA, BPAP, BPZ, DMBPA, and BPB also inhibited human 3β-HSD1 activity, albeit with lower potency. BPG was the most potent inhibitor of rat 3β-HSD4, with an IC₅₀ value of 1.14 μM. BPAP, BPFL, BPG, BPH, BPZ, DABPA, and DMBPA are mixed inhibitors of human 3β-HSD1 and they significantly inhibited human JAr cells to secrete progesterone. The LogP values were inversely correlated with the inhibitory effects. Docking analysis showed that most BPA analogues bind to steroid-binding site of both 3β-HSDs. A pharmacophore containing hydrogen bond donor and hydrophobic region was generated for predicting the inhibitory strength of BPA analogues. In conclusion, this study demonstrates that some BPA analogues are potent inhibitors of 3β-HSDs and lipophilicity determines the inhibitory potency.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111251"},"PeriodicalIF":4.7,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142309366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cuproptosis in microsatellite stable colon cancer cells affects the cytotoxicity of CD8+T through the WNT signaling pathway","authors":"Jintao Zeng ,&nbsp;Hong Chen ,&nbsp;Xing Liu ,&nbsp;Haoyun Xia ,&nbsp;Liqi Chen ,&nbsp;Dajia Lin ,&nbsp;Naisen Wang ,&nbsp;Chong Weng ,&nbsp;Guoxian Guan ,&nbsp;Yu Zheng","doi":"10.1016/j.cbi.2024.111239","DOIUrl":"10.1016/j.cbi.2024.111239","url":null,"abstract":"<div><div>The microsatellite stable (MSS) colon cancer (CC) has long been considered resistant to immunotherapy. Cuproptosis, as a novel form of cell death, may interact with tumor immunity. This project focused on the impact of cuproptosis on the cytotoxicity of CD8⁺T in MSS CC, aiming to provide effective clues for improving the treatment strategy of MSS CC. The study developed an MSS CC cuproptosis model using 50 nM elesclomol and 1 μM CuCl₂. Cuproptotic SW480 cells were directly co-cultured with CD8⁺ T cells. Cuproptosis levels were assessed via intracellular copper ion detection, Western blot, and confocal laser scanning microscopy. CCK-8, Hochest/PI staining, CFSE cell proliferation assay, LDH cytotoxicity detection, and ELISA were used to evaluate CD8⁺ T cell immune activity and cytotoxicity. Transcriptome sequencing and bioinformatics analysis identified regulated signals in cuproptotic SW480 cells. A rescue experiment utilized a WNT pathway activator (BML-284). PD-L1 expression in cells/membranes was analyzed using qRT-PCR, Western blot, and flow cytometry. NSG mice were immunoreconstituted, and the effects of cuproptosis on immune infiltration and cancer progression in MSS CC mice were assessed using ELISA and immunohistochemistry (IHC). Treatment with 50 nM elesclomol and 1 μM CuCl₂ significantly increased cuproptosis in SW480 cells. Co-culture with CD8⁺ T cells enhanced their cytotoxicity. Sequencing revealed cuproptosis-mediated modulation of immune and inflammatory pathways, including WNT signaling. Rescue experiments showed downregulation of WNT signaling in cuproptotic SW480 cells. Indirectly, CD8⁺ T cell immune function was enhanced by reducing PD-L1 expression. In mice, cuproptosis resulted in increased infiltration of CD8⁺ T cells in tumor tissue, leading to delayed cancer progression compared to the control group. Cuproptosis in MSS CC cells enhances the cytotoxicity of CD8⁺ T cells, which may be achieved through downregulation of the WNT signaling pathway and decreased expression of PD-L1. In the future, drugs that can induce cuproptosis may be a promising approach to improve MSS CC immunotherapy.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111239"},"PeriodicalIF":4.7,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiallodynic and antihyperalgesic effects of decursin associated with correcting mitochondrial dysfunction and oxidative stress in type 1 diabetic mice","authors":"Li Ma ,&nbsp;You-Ya Fan ,&nbsp;Ben-Ling Li ,&nbsp;Feng Xu ,&nbsp;Xin Zhao","doi":"10.1016/j.cbi.2024.111249","DOIUrl":"10.1016/j.cbi.2024.111249","url":null,"abstract":"<div><div>A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Decursin, a major active ingredient from <em>Angelica gigas</em> Nakai, has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of decursin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with decursin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although decursin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons, and restored nerve conduction velocity and blood flow in sciatic nerves. Notably, the analgesic actions of decursin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of decursin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111249"},"PeriodicalIF":4.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynine","authors":"Philip W. Melchert,&nbsp;Qingchen Zhang,&nbsp;John S. Markowitz","doi":"10.1016/j.cbi.2024.111247","DOIUrl":"10.1016/j.cbi.2024.111247","url":null,"abstract":"<div><div>Kratom (<em>Mitragyna Speciosa</em> Korth.) is an indigenous tree native to Southeast Asia whose leaves have been traditionally ingested as a tea and has seen its popularity increase in the United States. Although kratom and its constituents presently have no approved uses by the Food and Drug Administration, its major alkaloids (e.g., mitragynine) have psychoactive properties that may hold promise for the treatment of opioid cessation, pain management, and other indications. 9-O-demethylmitragynine is a major metabolite formed from mitragynine metabolism (36 % total metabolism) and displays similar pharmacologic activity. Cytochrome P450 (CYP) 3A4 has been identified as a major enzyme involved in mitragynine metabolism; however, the in vitro metabolism parameters of 9-O-demethylmitragynine formation are not well defined and a risk of potential drug interactions exists. Using human liver S9 fractions, 9-O-demethylmitragynine formation was generally linear for enzyme concentrations of 0–0.25 mg/mL and incubation times of 5–20 min. 9-O-demethylmitragynine displayed a K_m 1.37 μM and V_max of 0.0931 nmol/min/mg protein. Known CYP inhibitors and compounds that might be concomitantly used with kratom were assessed for inhibition of 9-O-demethylmitragynine formation. Ketoconazole, a CYP3A index inhibitor, demonstrated a significant effect on 9-O-demethylmitragynine formation, further implicating CYP3A4 as a major metabolic pathway. Major cannabinoids (10 μg/mL) displayed minor inhibition of 9-O-demethylmitragynine formation, while all other compounds had minimal effects. Mixtures of physiological achievable cannabinoid concentrations also displayed minor effects on 9-O-demethylmitragynine formation, making a metabolic drug interaction unlikely; however, further in vitro, in vivo, and clinical studies are necessary to fully exclude any risk.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111247"},"PeriodicalIF":4.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tyrosine kinase inhibitor Nintedanib induces lysosomal dysfunctionality: Role of protonation-dependent crystallization processes","authors":"Elena Mosca ,&nbsp;Anja Federa ,&nbsp;Christine Pirker ,&nbsp;Markus Schosserer ,&nbsp;Lisa Liendl ,&nbsp;Margret Eckhard ,&nbsp;Andy Sombke ,&nbsp;Orsolya Dömötör ,&nbsp;Dominik Kirchhofer ,&nbsp;Gerald Timelthaler ,&nbsp;Dina Baier ,&nbsp;Patrizia Gurschka ,&nbsp;Lisa Gabler ,&nbsp;Michael Reithofer ,&nbsp;Jia Min Chin ,&nbsp;Kareem Elsayad ,&nbsp;Bernhard Englinger ,&nbsp;Ammar Tahir ,&nbsp;Christian R. Kowol ,&nbsp;Walter Berger","doi":"10.1016/j.cbi.2024.111243","DOIUrl":"10.1016/j.cbi.2024.111243","url":null,"abstract":"<div><div>Nintedanib (NIN), a multi-tyrosine kinase inhibitor clinically approved for idiopathic pulmonary fibrosis and lung cancer, is characterized by protonation-dependent lysosomotropic behavior and appearance of lysosome-specific fluorescence emission properties. Here we investigate whether spontaneous formation of a so far unknown NIN matter within the acidic cell compartment is underlying these unexpected emissive properties and investigate the consequences on lysosome functionality. Lysosomes of cells treated with NIN, but not non-protonatable NIN derivatives, exhibited lysosome-associated birefringence signals co-localizing with the NIN-derived fluorescence emission. Sensitivity of both parameters towards vATPase inhibitors confirmed pH-dependent, spontaneous adoption of novel crystalline NIN structures in lysosomes. Accordingly, NIN crystallization from buffer solutions resulted in formation of multiple crystal polymorphs with pH-dependent fluorescence properties. Cell-free crystals grown at lysosomal-like pH conditions resembled NIN-treated cell lysosomes concerning fluorescence pattern, photobleaching dynamics, and Raman spectra. However, differences in birefringence intensity and FAIM-determined anisotropy, as well as predominant association with (intra)lysosomal membrane structures, suggested formation of a semi-solid NIN crystalline matter in acidic lysosomes. Despite comparable target kinase inhibition, NIN, but not its non-protonatable derivatives, impaired lysosomal functionality, mediated massive cell vacuolization, enhanced autophagy, deregulated lipid metabolism, and induced atypical phospholipidosis. Moreover, NIN exerted distinct phototoxicity, strictly dependent on lysosomal microcrystallization events. The spontaneous formation of NIN crystalline structures was also observable in the gut mucosa of orally NIN-treated mice. Summarizing, the here-described kinase inhibition-independent impact of NIN on lysosomal functionality mediates several of its cell biological activities and might contribute to NIN adverse effects.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111243"},"PeriodicalIF":4.7,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0009279724003892/pdfft?md5=0621747e1a340bf9ae3ff187281f9a5b&pid=1-s2.0-S0009279724003892-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of new non-covalent reversible BTK inhibitors: Synthesis, in silico studies, and in vitro evaluations","authors":"Zunyuan Wang ,&nbsp;Shu Wang ,&nbsp;Youkun Kang ,&nbsp;Xinglong Chi ,&nbsp;Youlu Pan ,&nbsp;Shenxin Zeng ,&nbsp;Chixiao Zhang ,&nbsp;Xiangwei Xu ,&nbsp;Wenyong Wang ,&nbsp;Wenhai Huang","doi":"10.1016/j.cbi.2024.111241","DOIUrl":"10.1016/j.cbi.2024.111241","url":null,"abstract":"<div><div>Bruton's Tyrosine Kinase (BTK) played a key role in the B cell antigen receptor (BCR) signaling pathway, and was considered a hotspot in the treatment of B cell malignant tumors and B cell immune diseases. There were 5 covalent irreversible inhibitors launched currently on the market, but C481S mutation was detected in most patients after administration. The approval of Pirtobrutinib (Jaypirca) by FDA in 2023 aroused great interest in the development of non-covalent and reversible BTK inhibitors. In order to solve the resistance of covalent irreversible inhibitors caused by C481S mutation, 11 reversible BTK inhibitors were designed based on screening in this article. The design, synthesis, <em>in silico</em> studies, and <em>in vitro</em> evaluations were performed for further verification. Among them, compound <strong>WS-11</strong> showed best activity with IC₅₀ of 3.9 nM for wild type, 2.2 nM for C481S mutation BTK, which was comparable to the positive control Pirtobrutinib. Furthermore, <strong>WS-11</strong> would have a good druglikeness properties predicted by pkCSM and SwissADME, which provided a promising lead for further optimization and development.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111241"},"PeriodicalIF":4.7,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}