Bioorganic & Medicinal Chemistry Letters最新文献_第2页

Discovery of 3-amide-pyrimidine-based derivatives as potential fms-like tyrosine receptor kinase 3 (FLT3) inhibitors for treating acute myelogenous leukemia.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-19 DOI: 10.1016/j.bmcl.2024.130082

Wei Liu, Yi Ma, Miaomiao Wang, Youyou He, Yanhong Liu, Zhenbao Zhu, Yi Ding, Ge Zhang, Shengzheng Wang

{"title":"Discovery of 3-amide-pyrimidine-based derivatives as potential fms-like tyrosine receptor kinase 3 (FLT3) inhibitors for treating acute myelogenous leukemia.","authors":"Wei Liu, Yi Ma, Miaomiao Wang, Youyou He, Yanhong Liu, Zhenbao Zhu, Yi Ding, Ge Zhang, Shengzheng Wang","doi":"10.1016/j.bmcl.2024.130082","DOIUrl":"10.1016/j.bmcl.2024.130082","url":null,"abstract":"FLT3-ITD and TKD mutants play a central role in acute myeloid leukemia (AML), making FLT3 an attractive target for AML treatment. To discover next-generation FLT3 inhibitors and gather additional structure-activity relationship (SAR) information, we performed structural modifications of G-749 (denfivontinib) utilizing structure simplification and scaffold hopping strategies. Among these derivatives, MY-10 exhibited the most potent and selective inhibition of MV4-11 cell proliferation, demonstrating potent inhibitory activity against FLT3-ITD (IC50 = 6.5 nM) and FLT3-D835Y (IC50 = 10.3 nM) mutants. Notably, MY-10 exhibited no inhibitory activity against c-KIT kinase (IC50 > 100 μM). Mechanistic studies revealed that MY-10 arrested the cell cycle at the G0/G1 phase and efficiently induced apoptosis. Furthermore, it significantly reduced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP), and strongly inhibited FLT3-mediated signaling pathways. These findings, along with the obtained SAR information, provide valuable insights for the further development of FLT3 inhibitors.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130082"},"PeriodicalIF":2.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870621","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

Synthesis and physiological effects of new 4-aminophenol derivatives as paracetamol analogues.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-18 DOI: 10.1016/j.bmcl.2024.130080

Maryna Lisouskaya, Olga A Antipova, Irina P Zhavoronok, Alexander Mikhalchuk

引用次数: 0

Docking and structure activity relationship studies of potent and selective thiazolidinethione GSK-3 inhibitors.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-16 DOI: 10.1016/j.bmcl.2024.130074

Hannah Boesger, Kurtis Williams, Sa Adatu Abdullai, Brianna Hubble, Mahboubeh S Noori, Crina Orac, Deborah K Amesaki, Davoud Ghazanfari, Emily A Fairchild, Opeyemi O Fatunbi, Joshua A Pritchard, Douglas J Goetz, Jennifer V Hines, Stephen C Bergmeier

引用次数: 0

Synthesis of dolutegravir derivatives modified by 1,2,3-triazole structure and their anti-inflammatory activity in LPS-induced BV2 cells.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-16 DOI: 10.1016/j.bmcl.2024.130076

Xixi Hou, Longfei Mao, Xuanwei Zhang, Xi Wang, Lan Wang, Jianji Wang

{"title":"Synthesis of dolutegravir derivatives modified by 1,2,3-triazole structure and their anti-inflammatory activity in LPS-induced BV2 cells.","authors":"Xixi Hou, Longfei Mao, Xuanwei Zhang, Xi Wang, Lan Wang, Jianji Wang","doi":"10.1016/j.bmcl.2024.130076","DOIUrl":"10.1016/j.bmcl.2024.130076","url":null,"abstract":"Given the promising anti-inflammatory activity of the HIV integrase inhibitor dolutegravir and the widespread use of the 1,2,3-triazole structure in anti-inflammatory drug development, this study aimed to enhance dolutegravir's efficacy by introducing a 1,2,3-triazole group. As a result, four series of dolutegravir derivatives were synthesized. Screening these derivatives for anti-inflammatory activity in microglial cells revealed that compound 6k demonstrated the most potent anti-inflammatory effect without significant cytotoxicity. Specifically, 6k significantly reduced the transcription levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Additionally, 6k decreased the LPS-induced overproduction of inflammatory mediators such as nitric oxide (NO), IL-6, and TNF-α. Further investigation into the upstream inflammatory enzymes iNOS and COX-2 showed that 6k markedly reduced their transcription and protein levels. To elucidate the mechanism underlying the anti-inflammatory effects of dolutegravir derivatives, it was found that compound 6k modulates microglial inflammation by inhibiting the phosphorylation and nuclear translocation of signal transducer and activator of transcription 1/3 (STAT1/3). Moreover, acute toxicity testing in mice indicated that compound 6k exhibited low toxicity, suggesting its potential as a lead compound for the treatment of neuroinflammation.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130076"},"PeriodicalIF":2.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851746","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

Design and evaluation of anaplastic lymphoma kinase degraders using a covalent fumarate handle.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-15 DOI: 10.1016/j.bmcl.2024.130075

Namsik Yu, Ji-Eun Lee, Seulki Park, Su Kyeong Yun, Do Hyun Ryu, Jung-Ae Kim, Jeong-Hoon Kim, Jong Yeon Hwang

{"title":"Design and evaluation of anaplastic lymphoma kinase degraders using a covalent fumarate handle.","authors":"Namsik Yu, Ji-Eun Lee, Seulki Park, Su Kyeong Yun, Do Hyun Ryu, Jung-Ae Kim, Jeong-Hoon Kim, Jong Yeon Hwang","doi":"10.1016/j.bmcl.2024.130075","DOIUrl":"10.1016/j.bmcl.2024.130075","url":null,"abstract":"Targeted protein degradation has emerged as a novel therapeutic paradigm in drug discovery. Despite the FDA approval of anaplastic lymphoma kinase (ALK) inhibitors, the pursuit of compounds with enhanced potency and prolonged efficacy remains crucial to mitigate inevitable adverse effects. In this context, we endeavored to develop ALK degraders utilizing FDA-approved ALK inhibitors-crizotinib, ceritinib, brigatinib, and alectinib-as ALK binders, along with 4-methoxyphenylfumarate as a covalent handle to bind to RNF126 E3 ligase. Among the synthesized compounds, dALK-3-derived from brigatinib-efficiently induced the proteasomal degradation of EML4-ALK and exhibited a 10-fold superior anti-proliferative effect on H3122 cells compared to brigatinib. However, the enhanced anti-proliferative activity of dALK-3 was found to be independent of RNF126, a presumed potential E3 ligase, suggesting the need for investigation of other components within the ubiquitin-proteasome system. Our findings further support the potential application of the fumarate moiety as a binder for E3 ligases in targeted protein degradation.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130075"},"PeriodicalIF":2.5,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833427","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

Development of 3-indolyl substituted phenyl pyrazolo-carboxamide hybrids as potential type II VEGFR-2 inhibitors and in vitro cytotoxicity studies. 将 3-吲哚基取代的苯基吡唑-甲酰胺杂交化合物开发为潜在的 II 型血管内皮生长因子受体-2 抑制剂并进行体外细胞毒性研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-12 DOI: 10.1016/j.bmcl.2024.130070

Durgesh Gurukkala Valapil, Geetanjali Devabattula, Aman Singh Barahdia, Chandraiah Godugu, Nagula Shankaraiah

{"title":"Development of 3-indolyl substituted phenyl pyrazolo-carboxamide hybrids as potential type II VEGFR-2 inhibitors and in vitro cytotoxicity studies.","authors":"Durgesh Gurukkala Valapil, Geetanjali Devabattula, Aman Singh Barahdia, Chandraiah Godugu, Nagula Shankaraiah","doi":"10.1016/j.bmcl.2024.130070","DOIUrl":"10.1016/j.bmcl.2024.130070","url":null,"abstract":"The progression of tumors is intricately linked to angiogenesis, the formation of new blood vessels, driven primarily by the release of growth factors such as Vascular Endothelial Growth Factor (VEGF). Targeting VEGF signaling through its receptor kinase (VEGFR-2) has emerged as a promising anti-angiogenic strategy for cancer therapy. In this study, we designed and synthesized a series of novel chemical entities based on 3-indolyl substituted phenyl pyrazole-carboxamides through docking studies upon considering the structure of sorafenib and its pattern of type II inhibition of VEGFR-2. Among the synthesized hybrids, 7b was able to significantly inhibit the growth of cancer cell lines, specifically against MCF-7 at 2.12 ± 0.19 μM. Compound 7b also efficiently inhibited VEGFR-2 kinase at a concentration of 2.83 ± 0.86 μM during the in vitro studies. Mechanistic studies revealed that 7b induced apoptosis evidenced by AO/EB, DAPI, and DCFDA staining, and its impact on the migratory ability of the cancer cells were also studied. These findings highlight the potential of 7b as a lead candidate for further development of anti-angiogenic therapies targeting VEGFR-2.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130070"},"PeriodicalIF":2.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823537","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

Neratinib derivative 7A induces apoptosis in colon cancer cells via the p53 pathway. 奈拉替尼衍生物 7A 通过 p53 通路诱导结肠癌细胞凋亡

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-12 DOI: 10.1016/j.bmcl.2024.130069

Zhi-Yu Liu, Ruo-Tong Liu, Wen-Hao Cheng, Bo-Yu Zhang, Xing-Yu Zhang, Ying Zhou, Xiao-Qing Ye, Chun-Yun Zhou, Xiu-Jun Wang, Qian Sun, Jing Ji

引用次数: 0

Deep mutational scanning-guided design of a high-affinity helix-loop-helix peptide targeting G-CSF receptor.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-10 DOI: 10.1016/j.bmcl.2024.130071

Masataka Michigami, Yuka Kanata, Chang Iou Ven, Ayana Oshima, Asako Yamaguchi-Nomoto, Takayoshi Kinoshita, Takatsugu Hirokawa, Ikuo Fujii

{"title":"Deep mutational scanning-guided design of a high-affinity helix-loop-helix peptide targeting G-CSF receptor.","authors":"Masataka Michigami, Yuka Kanata, Chang Iou Ven, Ayana Oshima, Asako Yamaguchi-Nomoto, Takayoshi Kinoshita, Takatsugu Hirokawa, Ikuo Fujii","doi":"10.1016/j.bmcl.2024.130071","DOIUrl":"10.1016/j.bmcl.2024.130071","url":null,"abstract":"At present, mid-sized binding peptides have emerged as a new class of drug modalities. We have de novo designed a helix-loop-helix (HLH) peptide (MW: ∼4,500), constructed phage-displayed libraries, and screened the libraries against a variety of disease-related proteins to successfully obtain molecular-targeting HLH peptides. The next essential step in developing HLH peptides into therapeutics involves affinity engineering to optimize binding affinity and specificity. Here, we demonstrate deep mutational scanning to improve binding affinity over 1000-fold for an HLH peptide (P8-2KA; KD = 380 nM) targeting granulocyte colony-stimulation factor receptor (G-CSFR). Site-saturation mutagenesis on the two helices was performed to produce a phage-displayed library that was screened against G-CSFR. The DNA sequences of mutants from the unselected and selected phage libraries were analyzed with next-generation sequencing. The enrichment ratio of each mutant was calculated from the sequencing data to identify beneficial mutations for G-CSFR binding. Grafting of the five beneficial mutations on P8-2KA dramatically increased the binding affinity (KD = 16 nM), while cyclization of the HLH peptide with an intramolecular disulfide bond further increased binding affinity for G-CSFR (KD = 0.18 nM). The combined strategy of phage-displayed library selection and deep mutational scanning-guided design generated high-affinity HLH peptides, emphasizing the potential of molecular-targeting HLH peptides as a new drug modality that serves as an alternative to antibodies.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130071"},"PeriodicalIF":2.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816633","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

Classifying covalent protein binders by their targeted binding site.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-10 DOI: 10.1016/j.bmcl.2024.130067

Walaa A Bedewy, John W Mulawka, Marc J Adler

{"title":"Classifying covalent protein binders by their targeted binding site.","authors":"Walaa A Bedewy, John W Mulawka, Marc J Adler","doi":"10.1016/j.bmcl.2024.130067","DOIUrl":"10.1016/j.bmcl.2024.130067","url":null,"abstract":"Covalent protein targeting represents a powerful tool for protein characterization, identification, and activity modulation. The safety of covalent therapeutics was questioned for many years due to the possibility of off-target binding and subsequent potential toxicity. Researchers have recently, however, demonstrated many covalent binders as safe, potent, and long-acting therapeutics. Moreover, they have achieved selective targeting among proteins with high structural similarities, overcome mutation-induced resistance, and obtained higher potency compared to non-covalent binders. In this review, we highlight the different classes of binding sites on a target protein that could be addressed by a covalent binder. Upon folding, proteins generate various concavities available for covalent modifications. Selective targeting to a specific site is driven by differences in the geometry and physicochemical properties of the binding pocket residues as well as the geometry and reactivity of the covalent modifier \"warhead\". According to the warhead reactivity and the nature of the binding region, covalent binders can alter or lock a targeted protein conformation and inhibit or enhance its activity. We survey these various modification sites using case studies of recently discovered covalent binders, bringing to the fore the versatile application of covalent protein binders with respect to drug discovery approaches.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130067"},"PeriodicalIF":2.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816630","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

Design and synthesis of N-(3-cyanothiophen-2-yl)-2-phenoxyacetamide-based α-glucosidase inhibitors.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-09 DOI: 10.1016/j.bmcl.2024.130068

Yi-Tong Chen, Bo-Wen Wan, Kai-Ming Wang, Kong-Kai Zhu, Ning Meng, Cheng-Shi Jiang, Juan Zhang

引用次数: 0