Bioorganic & Medicinal Chemistry Letters最新文献_第10页

Targeted design, synthesis, molecular simulation, ADME-T and in-vitro anticancer assessment of phenyl-substituted-thioxo-tetrahydro-pyrimidin-benzenesulfonamide derivatives as potential BRAFV600E/WT inhibitors 潜在BRAFV600E/WT抑制剂苯基取代-硫氧四氢嘧啶-苯磺酰胺衍生物的靶向设计、合成、分子模拟、ADME-T及体外抗癌评价

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-10-08 DOI: 10.1016/j.bmcl.2025.130431

Ankit Kumar Singh , Vineet Prajapati , Adarsh Kumar , Vimlendu Kumar Sah , Prateek Pathak , Mashooq A. Bhat , Mohamed A. Al-Omar , Amita Verma , Pradeep Kumar

BRAF is one of the most commonly mutated oncogenes in human cancers, with more than 90 % of mutations occurring at codon 600. Among these, BRAF^V600E is the most prevalent, accounting for nearly 90 % of all BRAF codon 600 mutations, while the less frequent variants are collectively referred to as BRAF^V600WT. BRAF mutations are reported across several cancers, with the highest frequency in malignant melanoma (70–90 %).

To target these mutations, a series of phenyl-substituted thioxo-tetrahydro-pyrimidine-benzenesulfonamide hybrids in the [αC-OUT/DFG-IN] conformation were designed. Fourteen derivatives were synthesized through multistep reactions and evaluated for ADME-T properties and in silico binding affinities using molecular docking, further validated by molecular dynamics (MD) simulations of the top-ranked compound. In addition, cytotoxic activity against melanoma cell lines was assessed, followed by kinase inhibition studies on the most potent derivatives against BRAF^V600E/WT.

All compounds exhibited favorable ADME-T and drug-like properties. Among them, AV05 demonstrated the highest binding affinity (−8.013 kcal/mol) and potent cytotoxic activity (IC₅₀ = 1.25 ± 0.57 μM), with BRAF^V600E inhibition (0.89 ± 0.78 μM) comparable to sorafenib (−6.189 kcal/mol; IC₅₀ = 0.90 ± 0.21 μM; inhibition = 0.10 ± 0.01 μM). In contrast, AV01 showed the strongest affinity for BRAF^V600WT (−4.954 kcal/mol) and kinase inhibition (0.93 ± 0.28 μM), relative to sorafenib (−12.241 kcal/mol; inhibition = 0.16 ± 0.01 μM). Collectively, computational and biological evaluations revealed that the synthesized hybrids exhibited higher selectivity and potency toward BRAF^V600E than BRAF^V600WT, with AV05 emerging as the most promising compound.

BRAF是人类癌症中最常见的突变癌基因之一，超过90% %的突变发生在密码子600处。其中以BRAFV600E最为普遍，占BRAF密码子600突变总数的近90% %，而频率较低的变异统称为BRAFV600WT。据报道，BRAF突变存在于几种癌症中，其中恶性黑色素瘤的频率最高（70- 90% %）。针对这些突变，设计了一系列[αC-OUT/DFG-IN]构象的苯基取代硫氧基-四氢嘧啶-苯磺酰胺杂合体。通过多步反应合成了14个衍生物，并通过分子对接评估了ADME-T性能和硅结合亲和性，并通过分子动力学（MD）模拟进一步验证了排名靠前的化合物。此外，评估了对黑色素瘤细胞系的细胞毒活性，随后对最有效的BRAFV600E/WT衍生物进行了激酶抑制研究。所有化合物均表现出良好的ADME-T和药物样性质。其中,AV05展示亲和力最高(-8.013 千卡每摩尔)和强大的细胞毒性活动(IC₅₀ =  1.25±0.57  μM),与BRAFV600E抑制(0.89 ±0.78  μM)与索拉非尼(-6.189 千卡每摩尔;IC₅₀ =  0.90±0.21  μM,抑制 =  0.10±0.01  μM)。相比之下,AV01显示BRAFV600WT的最强的亲和力(-4.954 千卡每摩尔),激酶抑制(0.93 ±0.28  μM),相对于索拉非尼(-12.241 千卡每摩尔;抑制 =  0.16±0.01  μM)。总体而言，计算和生物学评价表明，合成的杂交种对BRAFV600E表现出比BRAFV600WT更高的选择性和效力，其中AV05被认为是最有希望的化合物。

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引用次数: 0

Design and synthesis of guanidino derivatives of benzoate esters as SIRT6 inhibitors 苯甲酸酯类胍类衍生物SIRT6抑制剂的设计与合成。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-10-07 DOI: 10.1016/j.bmcl.2025.130430

Yongzhi Ma , Minni Ding , Kewang Yu , Siyu Wang , Siyuan Wang , Hao Cao , Huiming Hua , Dahong Li

SIRT6 is a key member of the Sirtuin family and plays a crucial role in regulating cellular metabolism, maintaining genomic stability, and influencing the aging process. SIRT6 inhibitors have garnered significant attention due to their potential therapeutic value in treating cancer, inflammation, and metabolic diseases. In this study, a high-throughput virtual screening approach, combined with FLUOR DE LYS detection, was employed to identify the guanidino benzoate ester compound Hit 13, which exhibits SIRT6 inhibitory activity. Subsequent structural optimization yielded a series of analogs. Among these, compounds 15, 25, and 27 demonstrated SIRT6 inhibitory activity and selectivity. Combination therapy, an emerging strategy in cancer treatment, has demonstrated promising efficacy. The combination of SIRT6 inhibitors with chemotherapy drugs can produce synergistic cytotoxic effects, reverse drug resistance, and has the potential to reduce chemotherapy doses while mitigating side effects. When compound 15 or 25 was combined with chemotherapy agents, they significantly enhanced the anti-proliferative effects of these drugs on tumor cells. This sensitization effect was particularly pronounced with doxorubicin, which reduced its IC₅₀ value against MCF-7 cells from 11 μM to 4 μM. Compounds 15 and 25 may serve as promising lead compounds for drug development targeting SIRT6.

SIRT6是Sirtuin家族的关键成员，在调节细胞代谢、维持基因组稳定性、影响衰老过程中起着至关重要的作用。SIRT6抑制剂因其在治疗癌症、炎症和代谢性疾病方面的潜在治疗价值而受到广泛关注。本研究采用高通量虚拟筛选方法，结合FLUOR DE LYS检测，对具有SIRT6抑制活性的胍基苯甲酸酯化合物Hit 13进行了鉴定。随后的结构优化产生了一系列类似物。其中化合物15、25和27表现出SIRT6的抑制活性和选择性。联合治疗是一种新兴的癌症治疗策略，已显示出良好的疗效。SIRT6抑制剂与化疗药物联合使用可产生协同细胞毒作用，逆转耐药，具有减少化疗剂量同时减轻副作用的潜力。当化合物15或25与化疗药物联合使用时，它们显著增强了这些药物对肿瘤细胞的抗增殖作用。阿霉素对MCF-7细胞的致敏效果特别明显，其对MCF-7细胞的IC50值从11 μM降到4 μM。化合物15和25可作为靶向SIRT6药物开发的先导化合物。

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引用次数: 0

In vitro comparison of the glycosidase inhibitory profile of isoiminosugars with their 1- and 5a-modified derivatives 异亚糖及其1-和5a修饰衍生物的糖苷酶抑制谱的体外比较。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-10-06 DOI: 10.1016/j.bmcl.2025.130426

Solveig Auranaune Markussen , Óscar López , Emil Lindbäck

Isoiminosugars are a group of glycomimetics known for being among the most potent glycosidase inhibitors, making them attractive as lead compounds in drug discovery. This review article summarizes how glycosidase inhibitory activities in in vitro assays are influenced by substituents attached to the 1- and 5a-positions of polyhydroxylated piperidine isoiminosugars, compared to their non-substituted parent compounds. Additionally, the review gives an overview of the glycosidase inhibitory properties of common iminosugars. It also discusses how these properties are affected when the nitrogen atom in iminosugars, which occupies the position of the endocyclic oxygen atom in monosaccharides, is relocated to the position of the anomeric carbon atom to form isoiminosugars.

异亚糖是一组糖仿制品，被认为是最有效的糖苷酶抑制剂之一，使它们作为药物发现的先导化合物具有吸引力。这篇综述文章总结了体外糖苷酶抑制活性是如何受到多羟基哌啶异亚氨基糖的1-和5a位置上的取代基的影响的，与它们的非取代的母体化合物相比。此外，综述了常见亚糖的糖苷酶抑制特性。还讨论了当亚胺糖中的氮原子在单糖中占据内环氧原子的位置时，将其重新定位到异亚胺糖的头基碳原子的位置时，这些性质是如何受到影响的。

引用次数: 0

Privileged scaffold repurposed: the evolving role of quinolone derivatives in antiviral therapy 特权支架的重新利用：喹诺酮类衍生物在抗病毒治疗中的演变作用。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-10-04 DOI: 10.1016/j.bmcl.2025.130427

Hui Xu , Baohu Li , Kai Tang , Jinfei Yang , Peng Zhan

Significant advancements have been made in the field of antiviral drug development; however, existing therapies still face considerable challenges regarding safety and efficacy. Moreover, with the frequent emergence of outbreaks caused by viruses such as SARS-CoV-2, monkeypox virus, and Chikungunya virus in recent years, there is an urgent need to develop novel antiviral drugs that are highly effective, low-toxic, and possess broad-spectrum activity against drug-resistant strains. Exploring antiviral agents from privileged structures has long been a tacit shortcut for researchers, and quinolone derivatives, as a class of privileged structures with diverse antiviral activities, have attracted extensive attention in recent years, providing a crucial material basis for the development of next-generation antiviral drugs. This review focuses on the discovery, mechanisms of action, potential clinical applications, and research progress of quinolone derivatives with typical structural characteristics or potent antiviral activity, aiming to provide insights for current and future antiviral drug research.

抗病毒药物开发领域取得了重大进展；然而，现有的治疗方法在安全性和有效性方面仍面临相当大的挑战。此外，随着近年来SARS-CoV-2、猴痘病毒、基孔肯雅病毒等病毒引起的疫情频繁出现，迫切需要开发高效、低毒、广谱抗耐药菌株的新型抗病毒药物。从特权结构中探索抗病毒药物一直是研究人员的一条隐性捷径，而喹诺酮类衍生物作为一类具有多种抗病毒活性的特权结构，近年来受到广泛关注，为开发下一代抗病毒药物提供了重要的物质基础。本文就喹诺酮类药物的发现、作用机制、临床应用前景及研究进展进行综述，旨在为当前和未来抗病毒药物的研究提供参考。

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引用次数: 0

Design and validation of the first-in-class PROTACs for targeted degradation of the immune checkpoint LAG-3 针对免疫检查点LAG-3靶向降解的同类首个PROTACs的设计和验证。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-10-04 DOI: 10.1016/j.bmcl.2025.130428

Nelson García Vázquez , Somaya A. Abdel-Rahman , Hossam Nada , Moustafa Gabr

Lymphocyte activation gene-3 (LAG-3) is an inhibitory immune checkpoint receptor that plays a central role in T cell exhaustion and immune evasion in cancer. While monoclonal antibodies targeting LAG-3 have entered clinical development, small molecule approaches remain largely unexplored. Here, we report the design and validation of the first-in-class PROTACs for targeted degradation of LAG-3. In this study, we repurposed a LAG-3-binding small molecule identified through DNA-encoded library (DEL) screening as the targeting ligand for a series of CRL4^CRBN-based PROTACs designed with varied linker lengths. Western blot analysis in Raji-LAG3 cells demonstrated that LAG-3 PROTAC-1 and LAG-3 PROTAC-3 induce potent, dose-dependent degradation of LAG-3, with DC₅₀ values of 0.27 μM and 0.42 μM, respectively. Molecular docking and molecular dynamics (MD) simulations revealed the LAG-3 binding mode of designed PROTACs and provided structural insights into PROTAC-mediated ternary complex formation. Collectively, this work establishes a proof-of-concept for chemical degradation of LAG-3 for the first time and paves the way for novel immunotherapeutic strategies.

淋巴细胞活化基因-3 （LAG-3）是一种抑制性免疫检查点受体，在癌症中的T细胞衰竭和免疫逃避中起核心作用。虽然靶向LAG-3的单克隆抗体已进入临床开发阶段，但小分子方法在很大程度上仍未被探索。在这里，我们报告了针对LAG-3的靶向降解的同类首创的PROTACs的设计和验证。在这项研究中，我们重新利用通过dna编码文库（DEL）筛选鉴定的lag -3结合小分子作为靶向配体，设计了一系列具有不同连接体长度的基于crl4crbn的PROTACs。Raji-LAG3细胞的Western blot分析表明，LAG-3 PROTAC-1和LAG-3 PROTAC-3诱导了LAG-3的强效、剂量依赖性降解，其DC50值分别为0.27 μM和0.42 μM。分子对接和分子动力学（MD）模拟揭示了设计的protac的LAG-3结合模式，并为protac介导的三元配合物形成提供了结构见解。总的来说，这项工作首次建立了LAG-3化学降解的概念验证，并为新的免疫治疗策略铺平了道路。

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引用次数: 0

Development and bio-evaluation of novel indolizine derivatives in FLT3 mutant acute myeloid leukemia cells 新型吲哚嗪衍生物在FLT3突变型急性髓系白血病细胞中的开发和生物评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-10-04 DOI: 10.1016/j.bmcl.2025.130429

Qianlu Xing , Jiangdong Li , Yanjiao Shen , Lu He , Xiaojuan Ma , Pei Huang , Qiang Huang , Yan Chen

Acute myeloid leukemia (AML) is a highly malignant blood tumor, and FLT3 serves as an important molecular target for the treatment of AML. Currently, FLT3 inhibitors still have issues of drug resistance and unsatisfactory clinical efficacy in the treatment of AML. Indolizine derivatives exhibit good antibacterial and antitumor biological activities. Based on the synthesis and identification of a library of multiple indolizine lead compounds and screening of their antitumor activities, we evaluated a novel indolizine derivative, 8h, which exhibited more sensitivity in inhibiting FLT3-mutated AML cells MV4-11 and MOLM13. 8h concentration-dependently induced apoptosis of MV4-11 cells, as well as cell cycle arrest and mitochondrial membrane potential reduction. Treatment with 8h downregulated the expression levels of FLT3 protein and downstream signaling proteins, and induced the activation of apoptosis-related proteins Caspase-3 and Caspase-9. The novel indolizine derivative 8h has a good inhibitory effect on FLT3-mutated AML cells and has the potential to become a FLT3 inhibitor.

急性髓系白血病（Acute myeloid leukemia， AML）是一种高度恶性的血液肿瘤，FLT3是治疗AML的重要分子靶点。目前，FLT3抑制剂在治疗AML中仍存在耐药和临床疗效不理想的问题。吲哚嗪衍生物具有良好的抗菌和抗肿瘤活性。基于多个吲哚嗪先导化合物的合成和鉴定，以及对其抗肿瘤活性的筛选，我们评估了一种新的吲哚嗪衍生物8h，它对flt3突变的AML细胞MV4-11和MOLM13具有更强的抑制敏感性。8h浓度依赖性诱导MV4-11细胞凋亡，细胞周期阻滞，线粒体膜电位降低。8h处理可下调FLT3蛋白及下游信号蛋白的表达水平，诱导凋亡相关蛋白Caspase-3和Caspase-9的活化。新型吲哚嗪衍生物8h对FLT3突变的AML细胞有良好的抑制作用，有可能成为FLT3抑制剂。

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引用次数: 0

Targeting NFE2L1 signalling with small molecules to protect against Ferroptosis 利用小分子靶向NFE2L1信号传导预防铁下垂。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-10-03 DOI: 10.1016/j.bmcl.2025.130425

Lucie Svobodová , Jindřich Sedláček , Zuzana Šmahelová , Pavel Majer , Aleš Machara , Klára Grantz Šašková

Ferroptosis is a regulated form of cell death characterized by lipid peroxidation and excessive reactive oxygen species (ROS) accumulation, which are driven primarily by iron dysregulation. It plays a critical role in neurodegeneration, cancer, and ischaemia-reperfusion injury, making its modulation a promising therapeutic strategy. NFE2L1 (nuclear factor erythroid 2-related factor 1) is a key transcription factor in cellular homeostasis that mitigates oxidative and proteotoxic stress by regulating antioxidant, cytoprotective and proteostasis-related genes. In this study, we designed and synthesized a series of bis(dimethoxybenzylidene)oxocyclohexylsulfonamides and sulfamides that robustly activate NFE2L1. At low micromolar concentrations, these compounds protect human neuroblastoma SH-SY5Y cells from the ferroptosis-inducing agents erastin, RSL3, and ferric ammonium citrate (FAC)-induced oxidative cell death, demonstrating their potential as NFE2L1-targeting cytoprotective agents.

铁死亡是一种受调节的细胞死亡形式，其特征是脂质过氧化和过多的活性氧（ROS）积累，主要由铁调节失调驱动。它在神经变性、癌症和缺血再灌注损伤中起关键作用，使其调节成为一种有前途的治疗策略。NFE2L1 （nuclear factor erythroid 2-related factor 1）是细胞内稳态的关键转录因子，通过调节抗氧化、细胞保护和蛋白质稳态相关基因来减轻氧化和蛋白质毒性应激。在本研究中，我们设计并合成了一系列双（二甲氧基苄基）氧环己基磺胺类化合物和对NFE2L1具有强活性的磺胺类化合物。在低微摩尔浓度下，这些化合物可以保护人神经母细胞瘤SH-SY5Y细胞免受铁中毒诱导剂erastin、RSL3和柠檬酸铁铵（FAC）诱导的氧化细胞死亡，显示出它们作为nfe2l1靶向细胞保护剂的潜力。

引用次数: 0

Discovery of novel VEGFR-2 inhibitors through virtual screening, synthesis and bioactivity evaluation 通过虚拟筛选、合成和生物活性评价发现新的VEGFR-2抑制剂

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-10-03 DOI: 10.1016/j.bmcl.2025.130423

Xi Gu , Linquan Li , Jianquan Yin , Zhili Zuo

Vascular endothelial growth factor receptor 2 (VEGFR-2) is an attractive antitumor target. By effectively inhibiting the overexpression of VEGFR-2, it suppresses the abnormal angiogenesis occurring within tumors. Although some inhibitors targeting VEGFR-2 have been identified, the drug resistance is an unignorable disadvantage to make the urgent need of new structure inhibitors. In this study, an innovative approach involving vast chemical space similarity searching was applied using sunitinib as a template to generate a series of structurally novel and synthetically accessible small molecules. A series robust virtual screening methods were employed to discover promising compounds for synthesis and evaluation of their kinase inhibitory activity against VEGFR-2. The results demonstrated that two of these compounds, GL-3 (IC₅₀ = 5.44 μM) and GL-1 (IC₅₀ = 13.4 μM), exhibited inhibitory activity against VEGFR-2. Subsequently, molecular dynamics simulations were conducted to investigate the interaction mechanisms of these active molecules with VEGFR-2. In summary, this study offers novel perspectives on the development of VEGFR-2 inhibitors and offers an innovative strategy for discovering novel anticancer drugs.

血管内皮生长因子受体2 （VEGFR-2）是一个有吸引力的抗肿瘤靶点。通过有效抑制VEGFR-2的过表达，抑制肿瘤内发生的异常血管生成。虽然已经发现了一些靶向VEGFR-2的抑制剂，但耐药是其不可忽视的缺点，迫切需要新的结构抑制剂。在这项研究中，我们采用了一种创新的方法，以苏尼替尼为模板，进行了大量的化学空间相似性搜索，生成了一系列结构新颖、可合成的小分子。采用一系列强大的虚拟筛选方法来发现有前途的化合物，用于合成和评估其对VEGFR-2的激酶抑制活性。结果表明，其中两个化合物GL-3 （IC50 = 5.44 μM）和GL-1 （IC50 = 13.4 μM）对VEGFR-2具有抑制活性。随后，通过分子动力学模拟研究这些活性分子与VEGFR-2的相互作用机制。总之，本研究为VEGFR-2抑制剂的开发提供了新的视角，并为发现新的抗癌药物提供了创新的策略。

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引用次数: 0

Discovery of a macrocyclic FAK inhibitor GZD-257 for treatment of glioblastoma 发现治疗胶质母细胞瘤的大环FAK抑制剂GZD-257。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-10-02 DOI: 10.1016/j.bmcl.2025.130424

Ting Wu, Yaqing Zuo, Kehui Chen, Ying Xu, Daili Wu, Yi Le, Li Liu, Longjia Yan

Glioblastoma (GBM) is a primary malignant brain tumor that seriously threatens human health. Focal adhesion kinase (FAK) is an important target for GBM drug research and regulates tumor cell proliferation, invasion, and drug resistance. Although a large number of FAK inhibitors have entered clinical research, there are few reports on the treatment of GBM with FAK inhibitors. Herein, TAE-226, the earliest FAK inhibitor to enter clinical trials, was used as the lead compound, and a macrocyclization-based structural optimization strategy was adopted to develop novel FAK inhibitors. The optimized macrocyclic compound GZD-257 exhibited excellent in vitro anti-GBM activity. The IC₅₀ values of GZD-257 against FAK, glioblastoma cells U118-MG, and U87-MG reached 14.30 nM, 1.64 μM, and 1.40 μM, respectively. Interestingly, the IC₅₀ value of GZD-257 against Pyk2 was 68.20 nM, which performed 4.77-fold selectivity with FAK. In addition, GZD-257 showed excellent blood-brain barrier (BBB) penetration, with a Pe value of 43.85, significantly higher than that of the positive control TAE-226 (24.18). Finally, flow cytometry studies indicated that GZD-257 could significantly induce apoptosis of U118-MG cells and arrest the cell cycle at the G2/M phase. Molecular docking studies suggested that GZD-257 was a highly promising ATP-competitive FAK inhibitor

胶质母细胞瘤（GBM）是严重威胁人类健康的原发性恶性脑肿瘤。Focal adhesion kinase （FAK）是GBM药物研究的重要靶点，调控肿瘤细胞的增殖、侵袭和耐药。虽然大量FAK抑制剂已进入临床研究，但关于FAK抑制剂治疗GBM的报道很少。本文以最早进入临床试验的FAK抑制剂TAE-226为先导化合物，采用基于大环化的结构优化策略开发新型FAK抑制剂。优化后的大环化合物GZD-257具有良好的体外抗gbm活性。GZD-257对FAK、胶质母细胞瘤细胞U118-MG和U87-MG的IC50值分别为14.30 nM、1.64 μM和1.40 μM。有趣的是，GZD-257对Pyk2的IC50值为68.20 nM，对FAK的选择性为4.77倍。GZD-257具有良好的血脑屏障（BBB）穿透性，Pe值为43.85，显著高于阳性对照TAE-226（24.18）。最后，流式细胞术研究表明，GZD-257能显著诱导U118-MG细胞凋亡，使细胞周期停留在G2/M期。分子对接研究表明GZD-257是一种非常有前途的atp竞争性FAK抑制剂。

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引用次数: 0

AI-assisted delivery of novel covalent WRN inhibitors from a non-covalent fragment screen 人工智能辅助递送从非共价片段筛选的新型共价WRN抑制剂。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-09-30 DOI: 10.1016/j.bmcl.2025.130421

Geoffrey M.T. Smith, Laksh Aithani, Charlotte E. Barrett, Alwin O. Bucher, Christopher D.O. Cooper, Sébastien L. Degorce, Andrew S. Doré, Catherine T. Fletcher, Sophie Huber, Rosemary Huckvale, Amanda J. Kennedy, Abigail A. Mornement, Mark Pickworth, Prakash Rucktooa, Conor C.G. Scully, Sarah E. Skerratt

Werner (WRN) helicase, has emerged as a promising therapeutic target for cancers associated with microsatellite instability (MSI). This letter describes the discovery of small molecule inhibitors from a fragment screen that occupy a cryptic, allosteric site of WRN helicase. Key findings include the identification of benzimidazole and amino-indazole scaffolds, exploiting their proximity to Cys727 via covalent modification. The use of our proprietary co-folding model DragonFold assisted the identification of novel WRN helicase inhibitors. These, together with near-neighbor profiling, offer tools for furthering the understanding of WRN and BLM helicase function, and potential therapeutic avenues for MSI-associated cancers.

Werner （WRN）解旋酶已成为微卫星不稳定性（MSI）相关癌症的一个有希望的治疗靶点。这封信描述了从片段筛选中发现的小分子抑制剂，这些抑制剂占据了WRN解旋酶的一个隐变构位点。主要发现包括鉴定苯并咪唑和氨基茚唑支架，利用它们通过共价修饰与Cys727的接近性。使用我们专有的共折叠模型DragonFold协助鉴定新的WRN解旋酶抑制剂。这些与近邻谱分析一起，为进一步了解WRN和BLM解旋酶功能提供了工具，并为msi相关癌症提供了潜在的治疗途径。

引用次数: 0