Journal of medicinal chemistry. 2025 May 20. doi: 10.1021/acs.jmedchem.4c03092 Q16.82025

Structure-Based Design of Potent and Selective MerTK Inhibitors by Modulating the Conformation of αC Helix

通过调节αC螺旋构象设计有效的选择性的MerTK抑制剂翻译改进

Yi-Hui Peng¹, Mu-Chun Li¹, Wan-Ching Yen¹, Teng-Kuang Yeh¹, Ching-Cheng Hsueh¹, Fu-Ming Kuo¹, You-Liang Lai¹, Ling Chang¹, Lung-Chun Lee¹, Pei-Yi Chen¹, Kuei-Jung Yen¹, Teng-Yuan Chang¹, Hsu-Yi Sun¹, Chun-Yu Chang¹, Su-Huei Hsieh¹, Chen-Ming Yang¹, Hsing-Pang Hsieh^{1 2}, Su-Ying Wu¹

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作者单位

¹ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Miaoli County, Zhunan Town 350, Taiwan, R.O.C.

² Department of Chemistry, National Tsing Hua University, Hsinchu City 300044, Taiwan, R.O.C.

DOI: 10.1021/acs.jmedchem.4c03092 PMID: 40391976

摘要中英对照阅读

Tumor-associated macrophages play an important role in cancer progression and immunosuppression, making their receptors promising therapeutic targets. MerTK, a TAM receptor, regulates macrophage efferocytosis and polarization, and its inhibition holds potential for tumor growth suppression and immune modulation. However, Tyro3, another TAM receptor, is involved in neurogenesis, highlighting the need to selectively target MerTK while avoiding Tyro3 inhibiti... ...点击完成人机验证后继续浏览

肿瘤相关巨噬细胞在癌症进展和免疫抑制中起着重要作用，使其受体成为有前景的治疗靶点。MerTK是一种TAM受体，调节巨噬细胞的摄取作用（efferocytosis）和极化，并且其抑制可能具有抑瘤生长和免疫调节的潜力。然而，另一种TAM受体Tyro3与神经发生有关，这强调了在避免引起神经毒性的前提下特异性靶向MerTK的必要性。在这项研究中，我们提出了一种通过调整αC螺旋构象动力学来设计选择性MerTK抑制剂的新策略。通过整合结构生物学、药物化学、蛋白质稳定性检测和分子对接研究，我们发现化合物11具有对MerTK的强大抑制作用和特异性。药代动力学评估及体内实验进一步揭示了化合物11作为潜在候选药物的发展前景。我们的研究不仅推进了对MerTK特异性机制的理解，还提出了通过靶向αC螺旋构象来设计选择性激酶抑制剂的策略。

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期刊名：Journal of medicinal chemistry

缩写：J MED CHEM

ISSN：0022-2623

e-ISSN：1520-4804

IF/分区：6.8/Q1

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Structure-Based Design of Potent and Selective MerTK Inhibitors by Modulating the Conformation of αC Helix

通过调节αC螺旋构象设计有效的选择性的MerTK抑制剂翻译改进

Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors

作为MerTK特异性抑制剂的桥环并嘧啶类化合物的发现

Effective Reaction-Based De Novo Strategy for Kinase Targets: A Case Study on MERTK Inhibitors

基于反应的从头开始策略有效用于激酶靶点的新药设计——以MERTK抑制剂为例

Correction to "Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069"

对“发现和基于结构设计强效的共价PPARγ反激动剂BAY-4931和BAY-0069”的纠正

Perspectives for the structure-based design of acetylcholinesterase reactivators

基于结构的乙酰胆碱酯酶复活剂设计展望

Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design

基于结构的轻链药物设计及高活性香豆素类免疫球蛋白轻链淀粉样原纤维稳定剂的发现

Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design

基于结构设计识别高选择性食欲肽1受体拮抗剂的研究

Structure-based ligand design of novel bacterial RNA polymerase inhibitors

基于结构的细菌RNA聚合酶抑制剂的新配体设计

Structure based design of 11β-HSD1 inhibitors

基于结构的11β-HSD1抑制剂设计

Discovery of a butyrylcholinesterase-specific probe via a structure-based design strategy

基于结构的药物设计发现乙酰胆碱酯酶特异性探针

Structure-Based Design of Potent and Selective MerTK Inhibitors by Modulating the Conformation of αC Helix

通过调节αC螺旋构象设计有效的选择性的MerTK抑制剂 翻译改进

Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors

作为MerTK特异性抑制剂的桥环并嘧啶类化合物的发现

Effective Reaction-Based De Novo Strategy for Kinase Targets: A Case Study on MERTK Inhibitors

基于反应的从头开始策略有效用于激酶靶点的新药设计——以MERTK抑制剂为例

Correction to "Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069"

对“发现和基于结构设计强效的共价PPARγ反激动剂BAY-4931和BAY-0069”的纠正

Perspectives for the structure-based design of acetylcholinesterase reactivators

基于结构的乙酰胆碱酯酶复活剂设计展望

Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design

基于结构的轻链药物设计及高活性香豆素类免疫球蛋白轻链淀粉样原纤维稳定剂的发现

Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design

基于结构设计识别高选择性食欲肽1受体拮抗剂的研究

Structure-based ligand design of novel bacterial RNA polymerase inhibitors

基于结构的细菌RNA聚合酶抑制剂的新配体设计

Structure based design of 11β-HSD1 inhibitors

基于结构的11β-HSD1抑制剂设计

Discovery of a butyrylcholinesterase-specific probe via a structure-based design strategy

基于结构的药物设计发现乙酰胆碱酯酶特异性探针

通过调节αC螺旋构象设计有效的选择性的MerTK抑制剂翻译改进