Journal of Medicinal Chemistry最新文献

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Discovery of the First Highly Selective 1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one MKK4 Inhibitor. 首个高选择性1,4-二氢吡啶[3,4-b]吡嗪-3(2H)- 1 MKK4抑制剂的发现

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-11 DOI: 10.1021/acs.jmedchem.5c00919

Leon Katzengruber,Pascal Sander,Stefan Zwirner,Alexander Rasch,Eric Eberlein,Roland Selig,Wolfgang Albrecht,Lars Zender,Stefan A Laufer

Due to limited treatment options, liver failure remains a major challenge in modern medicine. With the validation of mitogen-activated protein kinase kinase 4 (MKK4, also known as MEK4 or MAP2K4) as a regulator of hepatocyte regeneration, a promising target for curative treatment of degenerative liver diseases was recently identified via in vivo RNAi experiments. The field of small molecules targeting MKK4 is of growing interest. Several MKK4 inhibitors with differing scaffolds are known, but few have reasonable selectivity profiles and drug-like properties. To further explore the space of drug-like MKK4 scaffolds, we performed a broad screening campaign and identified BI-D1870 as a promising candidate. The dihydropteridinone BI-D1870 is an unselective ribosomal S6 kinase inhibitor with broad off-target activity. In the study presented herein, we report a successful off-to-on target strategy that led to the development of highly selective 1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one inhibitors of MKK4.

由于治疗选择有限，肝功能衰竭仍然是现代医学的主要挑战。随着丝裂原活化蛋白激酶激酶4 （MKK4，也称为MEK4或MAP2K4）作为肝细胞再生的调节因子的验证，最近通过体内RNAi实验确定了治疗退行性肝病的有希望的靶点。靶向MKK4的小分子领域越来越受到关注。几种具有不同支架的MKK4抑制剂是已知的，但很少有合理的选择性和药物样特性。为了进一步探索药物样MKK4支架的空间，我们进行了广泛的筛选活动，并确定BI-D1870是一个有希望的候选者。二氢蝶啶酮BI-D1870是一种具有广泛脱靶活性的非选择性核糖体S6激酶抑制剂。在本文提出的研究中，我们报告了一种成功的off-to-on靶标策略，该策略导致了高选择性1,4-二氢吡啶[3,4-b]吡嗪-3(2H)- MKK4抑制剂的开发。

引用次数: 0

Noncovalent Interaction Thresholds Control Translocation and Cytotoxicity: A Combined Computational–Experimental Study 非共价相互作用阈值控制易位和细胞毒性：一项计算-实验联合研究

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-11 DOI: 10.1021/acs.jmedchem.5c01196

Xianyu Song, Xianli Duan, Wenjun Xiang, Shuangliang Zhao

Designing membrane-permeable drugs requires a precise understanding of noncovalent interactions governing cellular uptake. We propose a molecular thermodynamic–dynamic (MTD) framework that quantifies interaction thresholds dictating permeation efficiency, using polychlorinated biphenyls (PCBs) as structurally tunable probes. Our results reveal that optimal permeability occurs within a defined differential binding energy (ΔG = −3.6 to −6.8 kcal/mol for H-/X-bonding), facilitating membrane translocation through a binding-flip mechanism. Beyond this range, excessive binding affinity (ΔG < −7.5 kcal/mol) leads to kinetic trapping at the membrane surface. Notably, the membrane permeation coefficients exhibit a strong linear correlation with differential binding energy (R² = 0.93), as revealed by five distinct transition states, including a rate-limiting vertical rotation step (ΔG = 2.4 kcal/mol). These findings yield two critical design principles: (i) intermediate differential binding (−4.0 to −5.0 kcal/mol) maximizes permeability, aligning with optimal ranges in FDA-approved membrane-permeable drugs, and (ii) targeted X-bonding modulation precisely controls membrane interaction specificity.

设计膜渗透药物需要精确理解控制细胞摄取的非共价相互作用。我们提出了一个分子热力学-动力学（MTD）框架，该框架使用多氯联苯（pcb）作为结构可调探针，量化决定渗透效率的相互作用阈值。我们的研究结果表明，最佳渗透性发生在定义的微分结合能范围内（ΔG =−3.6至−6.8 kcal/mol的H-/ x键），通过结合翻转机制促进膜易位。超出这个范围，过度的结合亲和力(ΔG <；−7.5 kcal/mol)导致膜表面的动力学捕获。值得注意的是，膜渗透系数与差结合能呈很强的线性相关（R2 = 0.93），这表明了5个不同的过渡态，包括一个限速的垂直旋转步骤（ΔG = 2.4 kcal/mol）。这些发现产生了两个关键的设计原则：(i)中间差异结合（- 4.0至- 5.0 kcal/mol）使通透性最大化，与fda批准的膜透性药物的最佳范围一致；（ii）靶向x键调节精确控制膜相互作用特异性。

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引用次数: 0

Lipid Droplet-Targeted NIR Polarity Probe for the Imaging of Acute Asthma In Vivo. 脂滴定向近红外极性探针在体内急性哮喘成像中的应用。

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-11 DOI: 10.1021/acs.jmedchem.5c01403

Mingyue Li,Yanmei Zhu,Linlin Hu,Jun Li,Jiyoung Yoo,Huamei Zhang,Zhaosheng Qian,Xucong Zhou,Jong Seung Kim,Jin Zhou

Polarity changes are significant indicators during inflammation. Acute lung injury (ALI) and asthma, both inflammatory lung diseases, necessitate the detection of these polarity changes for early diagnosis and treatment monitoring. We designed and synthesized a lipid droplet-targeting, polarity-dependent near-infrared fluorescent probe, MY-1, on the basis of an intramolecular charge-transfer mechanism to noninvasively detect these inflammatory conditions. The probe exhibits a consistent decrease in fluorescence intensity with an increase in solvent polarity, demonstrating excellent photostability and biocompatibility. Utilizing MY-1, we can differentiate between normal cells and cancer cells and successfully detect polarity changes targeting lipid droplets within the lungs of mice suffering from ALI and asthma. Furthermore, we can monitor the therapeutic effects of dexamethasone on asthmatic mice, confirming the clinical application potential of MY-1. In summary, we believe that MY-1 offers a novel and effective approach to the diagnosis of acute ALI and asthma.

极性变化是炎症期间的重要指标。急性肺损伤（ALI）和哮喘均为肺部炎症性疾病，需要检测这些极性变化以进行早期诊断和治疗监测。我们设计并合成了一种基于分子内电荷转移机制的脂滴靶向、极性依赖的近红外荧光探针MY-1，以无创检测这些炎症状况。探针的荧光强度随溶剂极性的增加而降低，表现出良好的光稳定性和生物相容性。利用MY-1，我们可以区分正常细胞和癌细胞，并成功检测到ALI和哮喘小鼠肺内针对脂滴的极性变化。此外，我们可以监测地塞米松对哮喘小鼠的治疗效果，证实了MY-1的临床应用潜力。总之，我们相信MY-1为急性ALI和哮喘的诊断提供了一种新颖有效的方法。

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引用次数: 0

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-10

Yong Ju, Huizhu Song, Yuelan He, Yingtung Lo, Zhipeng Fan and Jianzhong Lu*,

引用次数: 0

MD-4251: A First-in-Class Oral MDM2 Degrader Inducing Complete Tumor Regression with Single-Dose Administration. MD-4251：单剂量口服MDM2降降剂诱导肿瘤完全消退。

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-10 Epub Date: 2025-06-13 DOI: 10.1021/acs.jmedchem.5c00809

Ranjan Kumar Acharyya, Liyue Huang, Angelo Aguilar, Biao Hu, Longchuan Bai, Hoda Metwally, Donna McEachern, Wei Jiang, Yu Wang, Qiuxia Li, Bo Wen, Duxin Sun, Shaomeng Wang

MDM2 is a key negative regulator of the tumor suppressor p53 and an attractive target for cancer therapy. We report the discovery of MD-4251, the first orally efficacious MDM2 degrader developed using PROTAC technology. MD-4251 induces potent and rapid MDM2 degradation in RS4;11 cells (DC₅₀ = 0.2 nM; D_max = 96% at 2 h), leading to robust p53 activation. It selectively inhibits the growth of acute leukemia cell lines with wild-type p53, with minimal activity in p53 mutant lines. MD-4251 shows excellent oral bioavailability in mice, favorable metabolic stability, and no CYP or hERG liabilities. A single oral dose induces sustained MDM2 depletion and attains complete tumor regression in vivo. These results support MD-4251 as a promising therapeutic candidate for cancers through depletion of MDM2.

MDM2是肿瘤抑制因子p53的关键负调控因子，是癌症治疗的一个有吸引力的靶点。我们报告了MD-4251的发现，这是第一个使用PROTAC技术开发的口服有效的MDM2降解剂。MD-4251诱导RS4细胞(DC50 = 0.2 nM；Dmax = 96% (2 h)，导致p53的强劲激活。它选择性地抑制野生型p53的急性白血病细胞系的生长，对p53突变株的活性最小。MD-4251在小鼠中具有良好的口服生物利用度，良好的代谢稳定性，无CYP或hERG负担。单次口服剂量可诱导MDM2持续耗竭并在体内实现肿瘤完全消退。这些结果支持MD-4251作为一种有希望的通过MDM2耗竭治疗癌症的候选药物。

引用次数: 0

Research Progress in Targeting GSPT1: Molecular Glues, Bifunctional Degraders, and Antibody-Enabled Molecular Glues for Cancer Therapy. 靶向GSPT1：分子胶、双功能降解剂和抗体激活分子胶在癌症治疗中的研究进展。

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-10 Epub Date: 2025-06-26 DOI: 10.1021/acs.jmedchem.5c00783

Binbin Cheng, Yaping Wang, Yimeng Hong, Yingxing Zhou, Jianjun Chen, Chunlai Zeng

G1 to S phase transition 1 (GSPT1, also known as eRF3a) is a crucial translation termination factor that plays a vital role in acute myeloid leukemia (AML) and MYC-driven lung cancer. Degrading GSPT1 can induce apoptosis in cancer cells and reduce their viability, thus making GSPT1 a potential therapeutic target. This perspective aims to introduce the current research status of the mechanism of molecular glues targeting GSPT1, summarize the recent progress in and challenges for existing molecular glues, bifunctional degraders, and antibody-enabled molecular glues targeting GSPT1, and outline the development strategies for targeting GSPT1 in the treatment of cancer.

G1到S相变1 （GSPT1，也称为eRF3a）是一个重要的翻译终止因子，在急性髓性白血病（AML）和myc驱动的肺癌中起着至关重要的作用。降解GSPT1可诱导癌细胞凋亡，降低其生存能力，从而使GSPT1成为潜在的治疗靶点。本视角旨在介绍分子胶靶向GSPT1机制的研究现状，总结现有靶向GSPT1的分子胶、双功能降解剂和抗体激活分子胶的最新进展和面临的挑战，并概述靶向GSPT1治疗癌症的发展策略。

引用次数: 0

Endoplasmic Reticulum-Targeting Iridium(III) Complexes Induce Pyroptosis and Enhance Immunogenic Cell Death in MDA-MB-231 Cells 内质网靶向铱（III）复合物诱导MDA-MB-231细胞焦亡并增强免疫原性细胞死亡

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-10 DOI: 10.1021/acs.jmedchem.5c00883

Wei Wu, Jiaen Huang, Yuling Li, Jiaxi Chen, Xiaowei Kuang, Manzhen Ye, Rui Chen, Junli An, Zunnan Huang, Jing Sun

Cancer immunotherapy has revolutionized oncology by leveraging host immunity to eliminate malignant cells. In this study, five iridium(III) complexes (Ir1–Ir5) were synthesized and evaluated for their in vitro antitumor activity against various tumor cell lines. Among these, Ir4 and Ir5 exhibited the highest cytotoxicity and the most rapid cellular uptake in MDA-MB-231 cells. Colocalization experiments confirmed their accumulation in the endoplasmic reticulum (ER) and their ability to induce pyroptosis. Additionally, both complexes triggered ER stress, leading to increased calreticulin exposure on the cell surface, high-mobility group box 1 secretion, and ATP release, which collectively promoted immunogenic cell death. In vivo, a triple-dose Ir4 vaccine regimen significantly suppressed tumor growth compared to other treatment groups. These findings highlight the potential of Ir4-based novel triple-dose vaccination as a promising cancer immunotherapy strategy.

癌症免疫疗法通过利用宿主免疫来消除恶性细胞，彻底改变了肿瘤学。本研究合成了5种铱（III）配合物（Ir1-Ir5），并评价了它们对多种肿瘤细胞系的体外抗肿瘤活性。其中，Ir4和Ir5在MDA-MB-231细胞中表现出最高的细胞毒性和最快的细胞摄取。共定位实验证实了它们在内质网（ER）中的积累和诱导焦亡的能力。此外，这两种复合物都触发内质网应激，导致细胞表面钙调蛋白暴露增加，高迁移率的组盒1分泌和ATP释放，共同促进免疫原性细胞死亡。在体内，与其他治疗组相比，三剂量Ir4疫苗方案显著抑制肿瘤生长。这些发现突出了基于ir4的新型三剂量疫苗作为一种有前途的癌症免疫治疗策略的潜力。

引用次数: 0

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-10

Yihui Song, Xiangli Ren, Xinyu Yang, Jinbo Xiong, Wenwen Wang, Kai Tang* and Bin Yu*,

引用次数: 0

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-10

Yi Yang, Weiwei Li, Yanjia Zhao, Hanqing Xu, Xu Wang, Guode Zhao, Zixia Hu*, Ying Peng* and Jiang Zheng*,

引用次数: 0

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-07-10

Beibei Li, Pengyi Yan, Yao Liu, Xu Ouyang, Qingyang Xu, Jingying Zhang, Zufang Ba, Jie Liu, Yu Wang, Tingting Yang, Xueting Liu, Zhongwei Yu, Bingqian Ren, Liru Yuan, Yuhuan Zhao, Chao Zhong, Hui Liu, Yun Zhang, Sanhu Gou* and Jingman Ni*,

引用次数: 0

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