Journal of Medicinal Chemistry最新文献_第6页

N-Terminal Stabilization of Radiolabeled Neurotensin Analogues for Improved Tumor Uptake

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-20 DOI: 10.1021/acs.jmedchem.4c02844

Sacha Bodin, Tyrillshall S. T. Damiana, Santo Previti, Laure Balasse, Lina Ali, Emmanuelle Rémond, Vincent Nail, Frédéric Lamare, Elif Hindié, Benjamin Guillet, Delphine Vimont, Simone U. Dalm, Florine Cavelier, Clément Morgat

Peptide-based radiopharmaceuticals targeting neurotensin-receptor-1 (NTS₁) are mainly stabilized using chemical modifications at the NT[8–13] sequence, thus increasing the stability and the uptake of the corresponding radionuclide-macrocycle-linker-bioconjugate. We postulate that the introduction of the linker at the N-term part induces additional cleavage sites that can be further stabilized to achieve a prolonged uptake. Double (JMV 7259 and JMV 7222) and triple-stabilized neurotensin analogues (JMV 7258 and JMV 7490) were synthesized, radiolabeled, and evaluated on HT-29 cells (NTS₁⁺). Nanomolar NTS₁-affinity and high internalization rates were observed for all of the radiopharmaceuticals. Efflux was lower for radiolabeled JMV 7490. Consequently, [¹¹¹In]In-JMV 7490 showed uptake of 5.86 ± 0.86 and 3.65 ± 0.29% ID/g of tissue in HT-29 xenografts at 1 and 4 h, respectively. We have successfully shown that high and persistent uptake of NTS₁-positive tumor cells is achievable by stabilization of the N-term part. Efflux also appears to be a critical parameter for the successful targeting of NTS₁ using radiopharmaceuticals.

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引用次数: 0

Medicinal Chemistry: A Key Driver in Achieving the Global Sustainable Development Goals

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-20 DOI: 10.1021/acs.jmedchem.4c03016

Bianca Martinengo, Eleonora Diamanti, Elisa Uliassi, Maria Laura Bolognesi

In 2015, the United Nations officially launched the Sustainable Development Goals (SDGs) as “the blueprint to achieve a better and more sustainable future for all. They address the global challenges we face, including those related to poverty, inequality, climate change, environmental degradation, peace and justice. The 17 Goals are all interconnected, in order to leave no one behind, it is important that we achieve them all by 2030”. Here, we have embedded medicinal chemistry as a key player to achieve SDGs. We firmly believe that medicinal chemistry can and must contribute to a sustainable future and a better world with an improved quality of life for all. We have taken a critical look at each of the SDGs, dividing them into Priority and Foundational, and analyzed how medicinal chemistry has an impact on each of them. Although much has been done, we are determined to make progress in this area.

引用次数: 0

Discovery of Novel Sulfonylurea NLRP3 Inflammasome Inhibitor for the Treatment of Multiple Inflammatory Diseases

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-20 DOI: 10.1021/acs.jmedchem.4c02813

Yiting Liu, Qinxue Wang, Jinyu Ma, Jiyuan Li, Cuina Li, Xiong Xie, Qiannan Xiao, Cen Xie, Hong Liu, Ying Hong, Jiang Wang

NLRP3 inflammasome is critical in innate immunity and inflammatory responses. A series of novel sulfonylurea-based NLRP3 inflammasome inhibitors was designed and synthesized. Notably, compound 15 exhibited the potent NLRP3 inhibitory activity, effectively suppressing IL-1β secretion in THP-1 (IC₅₀ = 23 nM), demonstrating better efficacy compared to MCC950. It selectively inhibits NLRP3 activation by disrupting inflammasome assembly, with no effect on NLRC4 or AIM2 inflammasomes. Molecular docking showed that the 1-methyl-4-(methylamino)piperidine moiety forms a novel hydrogen bond with Asp662 in the hydrophilic region of NLRP3. Additionally, compound 15 displayed excellent pharmacokinetic properties with 99.6% oral bioavailability in mice. It exhibited superior efficacy in acute peritonitis and diabetic kidney disease models, surpassing MCC950. Tissue distribution studies confirmed that compound 15 specifically targeted the gut and showed efficacy in an IBD model, comparable to MCC950. These findings highlight compound 15 as a promising lead for novel oral NLRP3 inflammasome inhibitors.

NLRP3 炎症小体在先天免疫和炎症反应中至关重要。研究人员设计并合成了一系列基于磺酰脲类的新型 NLRP3 炎性体抑制剂。值得注意的是，化合物 15 具有强效的 NLRP3 抑制活性，能有效抑制 THP-1 中 IL-1β 的分泌（IC50 = 23 nM），与 MCC950 相比具有更好的疗效。它通过破坏炎性体的组装选择性地抑制 NLRP3 的活化，而对 NLRC4 或 AIM2 炎性体没有影响。分子对接显示，1-甲基-4-（甲氨基）哌啶分子与 NLRP3 亲水区的 Asp662 形成了新型氢键。此外，化合物 15 显示出优异的药代动力学特性，小鼠口服生物利用度高达 99.6%。它在急性腹膜炎和糖尿病肾病模型中的疗效优于 MCC950。组织分布研究证实，化合物 15 特别针对肠道，在肠道疾病模型中显示出与 MCC950 相当的疗效。这些研究结果突出表明，化合物 15 是一种新型口服 NLRP3 炎症小体抑制剂的有前途的先导化合物。

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引用次数: 0

Synthesis and In Vitro Profiling of Psilocin Derivatives: Improved Stability and Synthetic Properties

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-20 DOI: 10.1021/acs.jmedchem.4c02612

Julia Eklund, Ulf Bremberg, Jessica Larsson, Edvard Torkelsson, Johan Wennerberg, Symantha Zandelin, Luke R. Odell

As interest in using psilocybin therapy for treating mental health disorders intensifies, the need for efficient production methods becomes increasingly important. Current medical-grade psilocybin production is inefficient and relies on a complicated multistep synthesis. This study has explored and evaluated psilocin ester prodrugs and psilocin salts as potential alternatives to psilocybin, focusing on their ease of synthesis, chemical stability, and metabolic profiles. A diverse library of 15 psilocin ester prodrugs and six psilocin salts was synthesized and evaluated. The study successfully identified several psilocin ester prodrugs and psilocin salts that exhibited desirable characteristics, including storage and handling stability, rapid metabolic conversion to psilocin, and easy synthesis, with potential advantages over psilocybin. This research introduces viable options through psilocin ester compounds and psilocin salts, offering promising avenues for future development.

引用次数: 0

Discovery of HM-279, a Potent Inhibitor of ALK5 for Improving Therapeutic Efficacy of Cancer Immunotherapy

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-19 DOI: 10.1021/acs.jmedchem.4c02293

Mai Arai, Mitsuharu Hanada, Haruka Taniguchi, Fumio Nakajima, Hiroshi Ohmoto, Tsuyoshi Inoue, Kazuhito Naka, Masaaki Sawa

Activin receptor-like kinase 5 (ALK5) is a type I receptor serine/threonine kinase and responsible for the TGF-β signaling pathway. ALK5 is thought to be a key player in the tumor microenvironment to promote tumor progression by affecting the anticancer immunity. Therefore, ALK5 is an attractive drug target for modulating TGF-β signaling pathways to improve the therapeutic efficacy of cancer immunotherapy. We report the optimization of a series of thiazole analogues starting from lead compound 6, focusing on improving off-target selectivity. Compound 19f (HM-279) was identified as a potent ALK5 inhibitor with an acceptable off-target selectivity and favorable ADME/PK properties. Oral administration of HM-279 demonstrated antitumor activity in a CT26.WT colon carcinoma syngeneic mouse model as a single agent and in combination with the anti-PD-1 antibody through CD8⁺ T cell immunity.

引用次数: 0

Development of CD73 Inhibitors in Tumor Immunotherapy and Opportunities in Imaging and Combination Therapy

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-19 DOI: 10.1021/acs.jmedchem.4c02151

Chunyang Bi, Jimmy S. Patel, Steven H. Liang

CD73 is a member of the membrane-bound enucleotidase family, which catalyzes the extracellular hydrolysis of adenosine monophosphate (AMP) to produce anti-inflammatory and immunosuppressive adenosine. As a novel checkpoint protein, CD73 is overexpressed in the immune system of various tumors, where adenosine is abundantly enriched. A large number of monoclonal antibodies (mAbs), nucleotides, and non-nucleotides as potent CD73 inhibitors are being discovered, providing opportunities for novel tumor immunotherapy. Currently, 18 CD73 inhibitors are in clinical trials, showing promising results in combination therapy for various solid tumors. The development of CD73-specific companion positron emission tomography imaging ligands holds potential for facilitating diagnosis, patient selection, and treatment efficacy evaluation throughout the entire process of CD73-targeted therapeutic development.

引用次数: 0

Synthesis of an RBM39 Degrader That Downregulates CEP192 and Induces Disorganized Spindle Structures

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-19 DOI: 10.1021/acs.jmedchem.5c00534

Xilin Lyu, Xiancheng Wang, Dongze Lin, Yuhan Lu, Chenxu Wang, Ziqin Yan, Zhiyi Wang, Ying Cheng, Jing Cheng, Xuelian Ren, Yi Su, Shijie Zhang, Yi Chen, He Huang, Yujun Zhao

RBM39 is an essential component of the spliceosome, playing a critical role in maintaining mRNA integrity. Its depletion significantly exacerbates RNA splicing defects and demonstrates potent anticancer activity. To identify key effectors following RBM39 depletion, we employed a multiomics approach to directly compare two structurally distinct compounds, CB039 and Indisulam. Through proteomic analysis, RNA sequencing, and DepMap dependency assessment, CEP192 emerged as a crucial gene, exhibiting dependency in 96% of the 1,100 analyzed cancer cell lines. In eight cancer cell lines, treatment with both CB039 and Indisulam consistently induced CEP192 exon 42 skipping and reduced CEP192 protein levels. Mechanistically, either CB039 treatment or RNA interference-mediated CEP192 knockdown led to a significant increase in spindle disorganization, as well as chromosome condensation and failed segregation. In conclusion, our characterization of the downstream effects of RBM39 depletion provides novel insights into the therapeutic potential of RBM39 degraders.

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引用次数: 0

Discovery of AIC263282, a Hepatitis B Virus Capsid Assembly Modulator Ready for Candidate Profiling

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-18 DOI: 10.1021/acs.jmedchem.4c0283810.1021/acs.jmedchem.4c02838

Bernhard Lesch*, Alexander Birkmann, Susanne Bonsmann, Alastair Donald, Florian Engel, Thomas Goldner, Kamal Kumar, Tamara Pfaff, Andreas Urban, Holger Zimmermann, Alexandra E. Bosnidou, Estefanía del Castillo, Félix Cuevas, Elena Detta, Daniel Font, Jordi González García, Justine Raymond, Maria Ángeles Sarmentero, Arjen Cnossen, Wessel Sinnige, Jack C. Slootweg, Anita Wegert and Helmut Buschmann,

Hepatitis B Virus (HBV) infections remain a threat to the global public health. Nucleoside analogues remain the mainstay of therapy despite their discouraging cure rates achieved. Capsid assembly modulators (CAMs) have been at the center of HBV research, but despite having shown clinical efficacy on viral load in clinical studies, market entry has been elusive. Herein, we present the optimization program of our lead series. Setting our focus on potency, solubility, and hERG liability, these studies resulted in AIC263282, a new, potent capsid assembly modulator with improved physicochemical properties, which is ready for profiling as a preclinical candidate.

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引用次数: 0

Designing Macrocyclic Kinase Inhibitors Using Macrocycle Scaffold Hopping with Reinforced Learning (Macro-Hop)

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-18 DOI: 10.1021/acs.jmedchem.5c0008710.1021/acs.jmedchem.5c00087

Hong Liang, Shengjie Huang, Xinxin Xu, Zhao Yin, Muzammal Hussain, Xiaojuan Song, Jianqiao Yi, Yingqi He, Jing Guo, Zhengchao Tu, Zhang Zhang*, Yang Zhou* and Xiaoyun Lu*,

Macrocycles have gained significant attention in drug discovery, with over 70 macrocyclic compounds currently in clinical use. Despite this progress, the effective methods for designing macrocycles remain elusive. In this study, we present Macro-Hop, a reinforced learning framework designed to rapidly and comprehensively explore the macrocycle chemical space. Macro-Hop efficiently generates novel macrocyclic scaffolds that not only align with predefined physicochemical properties but also exhibit 3D structural similarities to a specified reference compound. As a proof of concept, we applied Macro-Hop to design a new series of macrocycle inhibitors targeting PDGFRα^D842 V kinase. The representative compound L7 exhibited high potency against PDGFRα^D842 V in both biochemical and cellular assays with IC₅₀ values of 23.8 and 2.1 nM, respectively. L7 effectively inhibited clinically relevant secondary mutants PDGFRα^{D842 V/G680R} (IC₅₀ = 64.1 nM) and PDGFRα^{D842 V/T674I} (IC₅₀ = 27.6 nM), highlighting the rapid effectiveness of wet-leb validation with Macro-Hop.

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引用次数: 0

Designing Macrocyclic Kinase Inhibitors Using Macrocycle Scaffold Hopping with Reinforced Learning (Macro-Hop)

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry

Pub Date : 2025-03-18 DOI: 10.1021/acs.jmedchem.5c00087

Hong Liang, Shengjie Huang, Xinxin Xu, Zhao Yin, Muzammal Hussain, Xiaojuan Song, Jianqiao Yi, Yingqi He, Jing Guo, Zhengchao Tu, Zhang Zhang, Yang Zhou, Xiaoyun Lu

Macrocycles have gained significant attention in drug discovery, with over 70 macrocyclic compounds currently in clinical use. Despite this progress, the effective methods for designing macrocycles remain elusive. In this study, we present Macro-Hop, a reinforced learning framework designed to rapidly and comprehensively explore the macrocycle chemical space. Macro-Hop efficiently generates novel macrocyclic scaffolds that not only align with predefined physicochemical properties but also exhibit 3D structural similarities to a specified reference compound. As a proof of concept, we applied Macro-Hop to design a new series of macrocycle inhibitors targeting PDGFRα^D842 V kinase. The representative compound L7 exhibited high potency against PDGFRα^D842 V in both biochemical and cellular assays with IC₅₀ values of 23.8 and 2.1 nM, respectively. L7 effectively inhibited clinically relevant secondary mutants PDGFRα^{D842 V/G680R} (IC₅₀ = 64.1 nM) and PDGFRα^{D842 V/T674I} (IC₅₀ = 27.6 nM), highlighting the rapid effectiveness of wet-leb validation with Macro-Hop.

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引用次数: 0