Drug Development Research最新文献_第4页

The mechanism of action and chemical synthesis of FDA newly approved drug molecules FDA 新批准药物分子的作用机制和化学合成

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-09-10 DOI: 10.1002/ddr.22260

Dan-Dan Shen, Yue-Lin Zhang, Xiang Li, Yi-Ru Bai, Jun-Feng Xiong, Dong-Jie Seng, Yao-Dong Zhang, Hong-Min Liu, Shuo Yuan, Li Yang

引用次数: 0

A thiourea-bridged 99mTc(CO)3-dipicolylamine-2-nitroimidazole complex for targeting tumor hypoxia: Utilizing metabolizable thiourea-bridge to improve pharmacokinetics 以肿瘤缺氧为靶点的硫脲桥接 99m锝（CO）3-二二甲胺-2-硝基咪唑复合物：利用可代谢的硫脲桥接改善药代动力学

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-09-10 DOI: 10.1002/ddr.22258

Sweety Mittal, Chandan Kumar, Laxmi Jha, Madhava B. Mallia

{"title":"A thiourea-bridged 99mTc(CO)3-dipicolylamine-2-nitroimidazole complex for targeting tumor hypoxia: Utilizing metabolizable thiourea-bridge to improve pharmacokinetics","authors":"Sweety Mittal, Chandan Kumar, Laxmi Jha, Madhava B. Mallia","doi":"10.1002/ddr.22258","DOIUrl":"https://doi.org/10.1002/ddr.22258","url":null,"abstract":"The 2-nitroimidazole based 99mTc-radiopharmaceuticals are widely explored for imaging tumor hypoxia. Radiopharmaceuticals for targeting hypoxia are often lipophilic and therefore, show significant uptake in liver and other vital organs. In this context, lipophilic radiopharmaceuticals with design features enabling faster clearance from liver may be more desirable. A dipicolylamine-NCS bifunctional chelator that could generate a thiourea-bridge up on conjugation to primary amine bearing molecule was used to synthesize a 2-nitroimidazole-dipicolyl amine ligand for radiolabeling with 99mTc(CO)3 core. Corresponding Re(CO)3-analogue was prepared to establish the structure of 2-nitroimidazole-99mTc(CO)3 complex prepared in trace level. The 2-nitroimidazole-99mTc(CO)3 complex showed a hypoxic to normoxic ratio of ~2.5 in CHO cells at 3 h. In vivo, the complex showed accumulation and retention in tumor with high tumor to blood and tumor to muscle ratio. The study demonstrated the utility of metabolizable thiourea-bridge in 2-nitroimidazole-99mTc(CO)3 complex in inducing faster clearance of the radiotracer from liver. The dipicolylamine-NCS bifunctional chelator reported herein can also be used for radiolabeling other class of target specific molecules with 99mTc(CO)3 core.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A new perspective on antiangiogenic antibody drug resistance: Biomarkers, mechanisms, and strategies in malignancies 抗血管生成抗体耐药性的新视角：恶性肿瘤的生物标记物、机制和策略。

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-09-08 DOI: 10.1002/ddr.22257

Chen Zhao, Yuan Zeng, Nannan Kang, Yu Liu

{"title":"A new perspective on antiangiogenic antibody drug resistance: Biomarkers, mechanisms, and strategies in malignancies","authors":"Chen Zhao, Yuan Zeng, Nannan Kang, Yu Liu","doi":"10.1002/ddr.22257","DOIUrl":"10.1002/ddr.22257","url":null,"abstract":"Drug resistance of malignant tumor leads to disease progression be the bottleneck in clinical treatment. Antiangiogenic therapy, which aims to “starve” the tumor by inhibiting angiogenesis, is one of the key strategies in clinical oncology treatments. Recently, dozens of investigational antibody drugs and biosimilars targeting angiogenesis have obtained regulatory approval for the treatment of various malignancies. Moreover, a new generation of bispecific antibodies based on the principle of antiangiogenesis are being advanced for clinical trial to overcome antiangiogenic resistance in tumor treatment or enhance the efficacy of monotherapy. Tumors often develop resistance to antiangiogenesis therapy, presenting as refractory and sometimes even resistant to new therapies, for which there are currently no effective management strategies. Thus, a detailed understanding of the mechanisms mediating resistance to antiangiogenesis antibodies is crucial for improving drug effectiveness and achieving a durable response to antiangiogenic therapy. In this review, we provide a novel perspective on the tumor microenvironment, including antibody structure, tumor stroma, and changes within tumor cells, to analyze the multifactorial reasons underlying resistance to antiangiogenesis antibodies. The review also enumerates biomarkers that indicate resistance and potential strategies for monitoring resistance. Furthermore, based on recent clinical and preclinical studies, we summarize potential strategies and translational clinical trials aimed at overcoming resistance to antiangiogenesis antibodies. This review provides a valuable reference for researchers and clinical practitioners involved in the development of new drugs or therapeutic strategies to overcome antiangiogenesis antibodies resistance.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22257","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fasudil attenuates syncytin-1-mediated activation of microglia and impairments of motor neurons and motor function in mice 法舒地尔可减轻 syncytin-1 介导的小胶质细胞激活以及小鼠运动神经元和运动功能损伤。

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-09-05 DOI: 10.1002/ddr.22254

Mei Mao, Wen Zeng, Yan Zheng, Wen Fan, Yuanrong Yao

{"title":"Fasudil attenuates syncytin-1-mediated activation of microglia and impairments of motor neurons and motor function in mice","authors":"Mei Mao, Wen Zeng, Yan Zheng, Wen Fan, Yuanrong Yao","doi":"10.1002/ddr.22254","DOIUrl":"10.1002/ddr.22254","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Syncytin-1 (Syn), an envelope glycoprotein encoded by the env gene of the human endogenous retrovirus-W family, has been resorted to be highly expressed in biopsies from the muscles from ALS patients; however, the specific regulatory role of Syn during ALS progression remains uncovered.In this study, C57BL/6 mice were injected with adeno-associated virus-overexpressing Syn, with or without Fasudil administration. The Syn expression was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry analysis. The histological change of anterior tibial muscles was determined by hematoxylin-eosin staining. Qualitative ultrastructural analysis of electron micrographs obtained from lumbar spinal cords was carried out. Serum inflammatory cytokines were assessed by enzyme linked immunosorbent assay (ELISA) assay and motor function was recorded using Basso, Beattie, and Bresnahan (BBB) scoring, climbing test and treadmill running test. Immunofluorescence and western blot assays were conducted to examine microglial- and motor neurons-related proteins.Syn overexpression significantly caused systemic inflammatory response, muscle tissue lesions, and motor dysfunction in mice. Meanwhile, Syn overexpression promoted the impairment of motor neuron, evidenced by the damaged structure of the neurons and reduced expression of microtubule-associated protein 2, HB9, neuronal nuclei and neuron-specific enolase in Syn-induced mice. In addition, Syn overexpression greatly promoted the expression of CD16/CD32 and inducible nitric oxide synthase (M1 phenotype markers), and reduced the expression of CD206 and arginase 1 (M2 phenotype markers). Importantly, the above changes caused by Syn overexpression were partly abolished by Fasudil administration.This study provides evidence that Syn-activated microglia plays a pivotal role during the progression of ALS.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132130","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}

引用次数: 0

Daidzin enhances memory and the antischizophrenia drug olanzapine's effects, possibly through the 5-HT2A and D2 receptor interaction pathways 戴德津可增强记忆力和抗精神分裂症药物奥氮平的作用，这可能是通过 5-HT2A 和 D2 受体相互作用途径实现的。

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-09-04 DOI: 10.1002/ddr.22259

Muhammad Torequl Islam, Raihan Chowdhury, Md. Shimul Bhuia, Brototi Chakrabarty, Neloy Kundu, Md. Showkot Akbor, Salehin Sheikh, Rokibul Islam Chowdhury, Siddique Akber Ansari, Irfan Aamer Ansari, Md. Amirul Islam

{"title":"Daidzin enhances memory and the antischizophrenia drug olanzapine's effects, possibly through the 5-HT2A and D2 receptor interaction pathways","authors":"Muhammad Torequl Islam, Raihan Chowdhury, Md. Shimul Bhuia, Brototi Chakrabarty, Neloy Kundu, Md. Showkot Akbor, Salehin Sheikh, Rokibul Islam Chowdhury, Siddique Akber Ansari, Irfan Aamer Ansari, Md. Amirul Islam","doi":"10.1002/ddr.22259","DOIUrl":"10.1002/ddr.22259","url":null,"abstract":"Schizophrenia affects identification and disturbs our thinking and motivational capacity. Long-term use of daidzin (DZN) is evident to enhance attention and memory in experimental animals. This study aimed to investigate the effect of DZN on Swiss mice. To check animals' attention, identification, thinking, and motivational ability, we performed behavioral studies using marble burying, dust removal, and trained swimming protocols. For this, a total of 36 male Swiss albino mice were randomly divided into six groups, consisting of 6 animals in each group, as follows: control (vehicle), DZN-1.25, DZN-2.5, DZN-5 mg/kg, olanzapine (OLN)-2, and a combination of DZN-1.25 with OLN-2. Additionally, in silico studies are also performed to understand the possible molecular mechanisms behind this neurological effect. Findings suggest that DZN dose-dependently and significantly (p < .05) increased marble burying and removed dust while reducing the time to reach the target point. DZN-1.25 was found to enhance OLN's effect significantly (p < .05), possibly via agonizing its activity in animals. In silico findings suggest that DZN has strong binding affinities of -10.1 and -10.4 kcal/mol against human serotonin 2 A (5-HT2A) and dopamine 2 (D2) receptors, respectively. Additionally, DZN exhibits favorable pharmacokinetic and toxicity properties. We suppose that DZN may exert its attention- and memory-enhancing abilities by interacting with 5-HT2A and D2 receptors. It may exert a synergistic antischizophrenia-like effect with the standard drug, OLN. Further studies are required to discover the exact molecular mechanism for this neurological function in animals.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132129","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}

引用次数: 0

Biphenylsulfonamides as effective MMP-2 inhibitors with promising antileukemic efficacy: Synthesis, in vitro biological evaluation, molecular docking, and MD simulation analysis 联苯磺酰胺类化合物是有效的 MMP-2 抑制剂，具有良好的抗白血病疗效：合成、体外生物学评价、分子对接和 MD 模拟分析。

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-09-04 DOI: 10.1002/ddr.22255

Sandip K. Baidya, Tarun Patel, Ambati Himaja, Suvankar Banerjee, Sanjib Das, Balaram Ghosh, Tarun Jha, Nilanjan Adhikari

{"title":"Biphenylsulfonamides as effective MMP-2 inhibitors with promising antileukemic efficacy: Synthesis, in vitro biological evaluation, molecular docking, and MD simulation analysis","authors":"Sandip K. Baidya, Tarun Patel, Ambati Himaja, Suvankar Banerjee, Sanjib Das, Balaram Ghosh, Tarun Jha, Nilanjan Adhikari","doi":"10.1002/ddr.22255","DOIUrl":"10.1002/ddr.22255","url":null,"abstract":"Overexpression of matrix metalloproteinase-2 (MMP-2) possesses a correlation with leukemia especially chronic myeloid leukemia (CML). However, no such MMP-2 inhibitor has come out in the market to date for treating leukemia. In this study, synthesis, biological evaluation, and molecular modeling studies of a set of biphenylsulfonamide derivatives as promising MMP-2 inhibitors were performed, focusing on their potential applications as antileukemic therapeutics. Compounds DH-18 and DH-19 exerted the most effective MMP-2 inhibition (IC50 of 139.45 nM and 115.16 nM, respectively) with potent antileukemic efficacy against the CML cell line K562 (IC50 of 0.338 µM and 0.398 µM, respectively). The lead molecules DH-18 and DH-19 reduced the MMP-2 expression by 21.3% and 17.8%, respectively with effective apoptotic induction (45.4% and 39.8%, respectively) in the K562 cell line. Moreover, both these compounds significantly arrested different phases of the cell cycle. Again, both these molecules depicted promising antiangiogenic efficacy in the ACHN cell line. Nevertheless, the molecular docking and molecular dynamics (MD) simulation studies revealed that DH-18 formed strong bidentate chelation with the catalytic Zn2+ ion through the hydroxamate zinc binding group (ZBG). Apart from that, the MD simulation study also disclosed stable binding interactions of DH-18 and MMP-2 along with crucial interactions with active site amino acid residues namely His120, Glu121, His124, His130, Pro140, and Tyr142. In a nutshell, this study highlighted the importance of biphenylsulfonamide-based novel and promising MMP-2 inhibitors to open up a new avenue for potential therapy against CML.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132128","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}

引用次数: 0

Starch-based “smart” nanomicelles: Potential delivery systems for doxorubicin 基于淀粉的 "智能 "纳米细胞：多柔比星的潜在输送系统

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-08-29 DOI: 10.1002/ddr.22253

Parteek Prasher, Mousmee Sharma

{"title":"Starch-based “smart” nanomicelles: Potential delivery systems for doxorubicin","authors":"Parteek Prasher, Mousmee Sharma","doi":"10.1002/ddr.22253","DOIUrl":"https://doi.org/10.1002/ddr.22253","url":null,"abstract":"Vesicular nanosystems are a cornerstone to the contemporary drug delivery paradigm owing to their ability to encapsulate a variety of drug molecules, which improves the overall pharmacokinetics and bioavailability of the cargo drug. These systems have proven potential in the delivery of hydrophobic chemotherapeutic “Doxorubicin” (DOX), which faces frequent challenge relating to its nonspecific interactions, dose-limiting toxicity (myelosuppression being the most common manifestation), and short half-life (distribution half-life of 5 min, terminal half-life of 20–48 h), which limit its overall clinical effectiveness. “Smart” nanomicelles with stimuli-responsive linkages take advantage of tumor microenvironment for deploying the cargo drug at the target site, which prevents nonspecific distribution and, hence, low toxicity. Similarly, those with stealth properties evade protein response, which triggers the immunogenic response. The nanomicelles co-loaded with magnetic nanoparticles provide additional utility such as contrast enhancement agents in theranostics. Overall, the starch-based nanomicelles prove to be an excellent delivery system for overcoming the limitations associated with the conventional DOX delivery regime.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100239","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}

引用次数: 0

Induction of apoptosis by oridonin in nonfunctioning pituitary adenoma cells 奥利多宁诱导无功能垂体腺瘤细胞凋亡

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-08-26 DOI: 10.1002/ddr.22251

Hui-Tong Chen, Xing-Yi Yuan, Zhong-Yu Wang, Dong Fan, Xiong-Ming Luo, Jun-Hua Yang, Yu-Xin Ma, Jing Liu, Xin Wang, Zong-Ming Wang

{"title":"Induction of apoptosis by oridonin in nonfunctioning pituitary adenoma cells","authors":"Hui-Tong Chen, Xing-Yi Yuan, Zhong-Yu Wang, Dong Fan, Xiong-Ming Luo, Jun-Hua Yang, Yu-Xin Ma, Jing Liu, Xin Wang, Zong-Ming Wang","doi":"10.1002/ddr.22251","DOIUrl":"10.1002/ddr.22251","url":null,"abstract":"Nonfunctioning pituitary adenoma (NFPA) is one of the major subtypes of pituitary adenomas (PA) and its primary treatment is surgical resection. However, normal surgery fails to remove lesions completely and there remains in lack of frontline treatment, so the development of new drugs for NFPA is no doubt urgent. Oridonin (ORI) has been reported to have antitumor effects on a variety of tumors, but whether it could exhibit the same effect on NFPA requires to be further investigated. The effects of ORI on pituitary-derived folliculostellate cell line (PDFS) cell viability, colony formation, proliferation ability, migration, and invasion were examined by Cell Counting Kit-8, colony formation assay, 5‑Ethynyl‑2'‑deoxyuridine proliferation assay, wound-healing assay, and Transwell assay. The differentially expressed genes in the control and ORI-treated groups were screened by transcriptome sequencing analysis and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Cell cycle analysis was performed to detect changes in cell cycle. Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to detect apoptosis in ORI-treated cells. Western blot assay was performed to detect Bax, Bcl-2, and cleaved Caspase-3 protein expression. ORI inhibited PDFS cell viability and significantly suppressed cell proliferation, migration, and invasion. GO and KEGG results showed that ORI was associated with signaling pathways such as cell cycle and apoptosis in PDFS cells. In addition, ORI blocked cells in G2/M phase and induced apoptosis in PDFS cells. ORI can trigger cell cycle disruption and apoptosis collaboratively in PDFS cells, making it a promising and effective agent for NFPA therapy.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072337","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}

引用次数: 0

Diphenyl urea-benzylidene acetohydrazide hybrids as fibroblast growth factor receptor 1 inhibitors and anticancer agents 作为成纤维细胞生长因子受体 1 抑制剂和抗癌剂的二苯基脲-亚苄基乙酰肼混合物。

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-08-24 DOI: 10.1002/ddr.22249

Heba T. Abdel-Mohsen, Amira M. Nageeb, Iman A. Y. Ghannam

{"title":"Diphenyl urea-benzylidene acetohydrazide hybrids as fibroblast growth factor receptor 1 inhibitors and anticancer agents","authors":"Heba T. Abdel-Mohsen, Amira M. Nageeb, Iman A. Y. Ghannam","doi":"10.1002/ddr.22249","DOIUrl":"10.1002/ddr.22249","url":null,"abstract":"Molecular hybridization between diphenyl urea and benzylidene acetohydrazide was adopted for the design of a new series of FGFR-1 targeting cancer. The designed series was synthesized and submitted to NCI-USA to be screened for their growth inhibitory activity on NCI cancer cell lines. Some of the synthesized hybrids displayed promising growth inhibitory activity on NCI cancer cell lines with a mean GI% between 70.39% and a lethal effect. Compounds 9a, 9i, 9j, and 9n-p were further selected for a five-dose assay and all the tested candidates showed promising antiproliferative activity with GI50 reaching the submicromolar range. Encouraged by the potent activity of 9a on colon cancer on the one hand and the well-known overexpression of FGFR-1 in it on the other hand, it was further selected as a representative example to be evaluated for its mechanism on the cell cycle and apoptosis of HCT116 cell line. Interestingly, 9a was found to pause the cell cycle of the HCT116 cell line at the G1 phase and induced late apoptosis. In parallel, all the synthesized hybrids 9a-p were examined for their potential to inhibit FGFR-1 at 10 µM. Compounds 9a, 9g, 9h, and 9p were found to have potent inhibitory activity with % inhibition = 63.04%, 58.31%, 60.87% and 79.84%, respectively. Molecular docking simulation of 9a in the binding pocket of FGFR-1 confirms its capability to achieve the characteristic interactions of the type II FGFR-1 inhibitors. Exploration of the ADME properties of 9a-p by SwissADME web tool proved their satisfactory physicochemical properties for the discovery of new anticancer hits.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046459","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}

引用次数: 0

Tirbanibulin (KX2-391) analog KX2-361 inhibits botulinum neurotoxin serotype A mediated SNAP-25 cleavage in pre- and post-intoxication models in cells Tirbanibulin（KX2-391）类似物 KX2-361 在细胞中毒前和中毒后模型中抑制 A 血清型肉毒杆菌神经毒素介导的 SNAP-25 分裂。

IF 3.5 4区医学

Drug Development Research Pub Date : 2024-08-21 DOI: 10.1002/ddr.22248

Dilara Koc, Kubra Ibis, Peri Besarat, Erden Banoglu, Erkan Kiris

{"title":"Tirbanibulin (KX2-391) analog KX2-361 inhibits botulinum neurotoxin serotype A mediated SNAP-25 cleavage in pre- and post-intoxication models in cells","authors":"Dilara Koc, Kubra Ibis, Peri Besarat, Erden Banoglu, Erkan Kiris","doi":"10.1002/ddr.22248","DOIUrl":"10.1002/ddr.22248","url":null,"abstract":"Botulinum neurotoxins (BoNT) inhibit neuroexocytosis, leading to the potentially lethal disease botulism. BoNT serotype A is responsible for most human botulism cases, and there are no approved therapeutics to treat already intoxicated patients. A growing body of research has demonstrated that BoNT/A can escape into the central nervous system, and therefore, identification of BoNT/A inhibitors that can penetrate BBB and neutralize the toxin within intoxicated neurons would be important. We previously identified an FDA-approved, orally bioavailable compound, KX2-391 (Tirbanibulin) that inhibits BoNT/A in motor neuron assays. Recently, a structural analog of KX2-391, KX2-361, has been shown to exhibit good oral bioavailability and cross BBB with high efficiency in mouse experiments. Therefore, in this work, we evaluated the inhibitory effects of KX2-361 against BoNT/A. Toward this goal, we first evaluated the compound for its effects on cell viability in PC12 cells, via MTT assay, and in mouse embryonic stem cell (mESC)-derived motor neurons, with imaging-based assays. Following, we tested KX2-361 in mESC-derived motor neurons intoxicated with BoNT/A holotoxin, and the compound exhibited activity against the toxin in both pre- and post-intoxication conditions. Excitingly, KX2-361 also inhibited BoNT/A enzymatic component (light chain; LC) in PC12 cells transfected with BoNT/A LC. Furthermore, our molecular docking analyses suggested that KX2-361 can directly bind to BoNT/A LC. Medicinal chemistry approaches to develop structural analogs of KX2-361 to increase its efficacy against BoNT/A may provide a critical lead compound with BBB penetration capacity for drug development efforts against BoNT/A intoxication.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22248","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0