更新于：2024-11-01

PDGFRβ

更新于：2024-11-01

基本信息

别名

血小板源生长因子β受体、Beta platelet-derived growth factor receptor、Beta-type platelet-derived growth factor receptor

+ [13]

简介

Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor.

关联

项与 PDGFRβ 相关的药物

Tivozanib

替沃扎尼

靶点

PDGFRβ x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit

作用机制

PDGFRβ抑制剂 [+4]

在研机构

AVEO Pharmaceuticals, Inc. [+3]

原研机构

Kyowa Kirin Co., Ltd.

在研适应症

肾细胞癌 [+5]

非在研适应症

晚期肝细胞癌 [+10]

最高研发阶段批准上市

首次获批国家/地区

欧盟 [+3]

首次获批日期2017-08-24

Regorafenib

瑞戈非尼

靶点

ABL x BRAF x BRAF V600E x CRAF x CSF-1R x DDR2 x EphA2 x FGFR1 x FGFR2 x FRK x MAPK11 x PDGFRα x PDGFRβ x RET x Tie-2 x TrkA x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit

作用机制

ABL 抑制剂 [+19]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2012-09-27

Pazopanib Hydrochloride

培唑帕尼

靶点

FGFR1 x FGFR3 x Flt3L x ITK x LCK x PDGFRα x PDGFRβ x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit

作用机制

FGFR1拮抗剂 [+10]

在研机构

Novartis Pharmaceuticals Corp. [+3]

原研机构

GSK Plc

在研适应症

肾细胞癌 [+6]

非在研适应症

前列腺腺癌 [+88]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2009-10-19

2,230

项与 PDGFRβ 相关的临床试验

NCT06643143 / Not yet recruiting临床2期

A Randomized, Double-Blind, Placebo-Controlled Trial of IkT-001Pro in Pulmonary Arterial Hypertension

This is a randomized, double-blind, multi-center, placebo-controlled dose-ranging clinical trial of two IkT-001Pro doses in patients with PAH designed to assess safety, tolerability and efficacy. It will enroll approximately 150 participants at up to 50 sites globally. The study consists of two parts, a 26 week placebo controlled treatment period (Part A) followed by a 36 month extension period (Part B).

开始日期2025-06-30

申办/合作机构

Inhibikase Therapeutics, Inc.

NCT06454409 / Not yet recruiting临床1期IIT

A Phase 1b Study of the Multi-Kinase Inhibitor Regorafenib in Combination With the BCL-2 Inhibitor Venetoclax Plus Azacitidine in Patients With Relapsed/Refractory Acute Myeloid Leukemia

This phase Ib trial tests the safety, side effects, best dose and effectiveness of regorafenib in combination with venetoclax and azacitidine in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Regorafenib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps to slow or stop the spread of cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Giving regorafenib in combination with venetoclax and azacitidine may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.

开始日期2025-03-20

申办/合作机构

City of Hope National Medical Center

[+1]

NCT06124157 / Not yet recruiting临床3期IIT

A Randomized International Phase 3 Trial of Imatinib and Chemotherapy With or Without Blinatumomab in Patients With Newly-Diagnosed Philadelphia Chromosome-Positive or Philadelphia Chromosome-Like ABL-Class B-Cell Acute Lymphoblastic Leukemia

This phase III trial compares the effect of the combination of blinatumomab with dasatinib and standard chemotherapy versus dasatinib and standard chemotherapy for treating patients with Philadelphia chromosome positive (PH+) or Philadelphia chromosome-like (Ph-Like) ABL-class B-Cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a bispecific antibody that binds to two different proteins-one on the surface of cancer cells and one on the surface of cells in the immune system. An antibody is a protein made by the immune system to help fight infections and other harmful processes/cells/molecules. Blinatumomab may bind to the cancer cell and a T cell (which plays a key role in the immune system's fighting response) at the same time. Blinatumomab may strengthen the immune system's ability to fight cancer cells by activating the body's own immune cells to destroy the tumor. Dasatinib is in a class of medications called tyrosine kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply, which may help keep cancer cells from growing. Giving blinatumomab and dasatinib in combination with standard chemotherapy may work better in treating patients with PH+ or Ph-Like ABL-class B-ALL compared to dasatinib and chemotherapy alone.

开始日期2025-02-28

申办/合作机构

National Cancer Institute

100 项与 PDGFRβ 相关的临床结果

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100 项与 PDGFRβ 相关的转化医学

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0 项与 PDGFRβ 相关的专利（医药）

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4,536

项与 PDGFRβ 相关的文献（医药）

2025-02-01·Neural Regeneration Research

Subretinal fibrosis secondary to neovascular age-related macular degeneration: mechanisms and potential therapeutic targets

Article

作者: Zhao, Jiwei ; Ding, Quanju ; Zhang, Jingfa ; Wang, Yujun ; Zhang, Jingxiang ; Sheng, Xia

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration. It causes local damage to photoreceptors, retinal pigment epithelium, and choroidal vessels, which leads to permanent central vision loss of patients with neovascular age-related macular degeneration. The pathogenesis of subretinal fibrosis is complex, and the underlying mechanisms are largely unknown. Therefore, there are no effective treatment options. A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments. The current article reviews several aspects of subretinal fibrosis, including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis; multimodal imaging techniques for subretinal fibrosis; animal models for studying subretinal fibrosis; cellular and non-cellular constituents of subretinal fibrosis; pathophysiological mechanisms involved in subretinal fibrosis, such as aging, infiltration of macrophages, different sources of mesenchymal transition to myofibroblast, and activation of complement system and immune cells; and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis, such as vascular endothelial growth factor, connective tissue growth factor, fibroblast growth factor 2, platelet-derived growth factor and platelet-derived growth factor receptor-β, transforming growth factor-β signaling pathway, Wnt signaling pathway, and the axis of heat shock protein 70–Toll-like receptors 2/4–interleukin-10. This review will improve the understanding of the pathogenesis of subretinal fibrosis, allow the discovery of molecular targets, and explore potential treatments for the management of subretinal fibrosis.

2025-01-01·Experimental Neurology

Cold atmospheric plasma-activated saline alleviates secondary injury post-SCI by inhibiting extracellular matrix remodeling and infiltration of proinflammatory macrophages

Article

作者: Yang, Chunjun ; Zhang, Sheng-Quan ; Li, Jianjian ; Wang, Liyun ; Yang, Chun-Jun ; Zhang, Shengquan ; Zhou, Yun ; Feng, Xiaojun ; Liu, Yi ; Li, Jian-Jian ; Wang, Li-Yun ; Feng, Xiao-Jun ; Jiang, Yan

BACKGROUNDCold atmospheric plasma (CAP) has been shown to improve the recovery of transected peripheral nerves. We determined the protective role of CAP-activated saline (CAP-AS) treatment in the acute and subacute stages of spinal cord injury (SCI) in mice.METHODSC57BL/6 SCI mice were treated with CAP-AS for 14 days. Injury recovery was assessed weekly for four weeks by conducting motor function tests, including the Basso Mouse Scale (BMS) and footprint test. Transcriptome analysis was conducted on day 14 to elucidate potential mechanisms, which were further validated through immunofluorescence examinations of the injured spinal cord tissues on day 28 and the levels of proinflammatory cytokines produced by macrophages in vitro.RESULTSCompared to the SCI group, the CAP-AS-treated groups presented significantly better hindlimb motor function after four weeks. The downregulated (SCI vs. SCI + CAP-AS, with CAP-AS activated for 20 min) differentially expressed genes (DEGs) were enriched in the extracellular region, extracellular matrix (ECM), and ECM-receptor interaction. In contrast, the upregulated DEGs were enriched in immune response-associated pathways. Histological changes in the CAP-AS-treated groups were observed to further validate the predicted mechanisms 28 days post-injury. The alleviation of secondary injury was confirmed by an increase in GFAP-positive and NFH-positive areas, and enhanced outgrowth of 5-HT-positive fibers. Inhibited ECM remodeling was confirmed by a decrease in the areas positive for PDGFRβ, fibronectin, and laminin. A decrease in the infiltration of macrophages and activation of microglia was determined by a decrease in CD68-positive and F4/80-positive areas. The inhibitory effect of CAP-AS on inflammation was further supported by a decrease in the levels of the proinflammatory cytokines IL-1β, IL-6, and TNF-α in CAP-AS-treated M1 macrophages.CONCLUSIONCAP-AS can alleviate secondary injury in SCI model mice by inhibiting ECM remodeling in injured tissues and reducing the infiltration or activation of proinflammatory macrophages/microglia.

2024-12-01·Cellular and Molecular Life Sciences

Endothelial PDGF-D contributes to neurovascular protection after ischemic stroke by rescuing pericyte functions

Article

作者: Menet, Romain ; ElAli, Ayman ; Lecordier, Sarah ; Bernard, Maxime

AbstractIschemic stroke induces neovascularization of the injured tissue as an attempt to promote structural repair and neurological recovery. Angiogenesis is regulated by pericytes that potently react to ischemic stroke stressors, ranging from death to dysfunction. Platelet-derived growth factor (PDGF) receptor (PDGFR)β controls pericyte survival, migration, and interaction with brain endothelial cells. PDGF-D a specific ligand of PDGFRβ is expressed in the brain, yet its regulation and role in ischemic stroke pathobiology remains unexplored. Using experimental ischemic stroke mouse model, we found that PDGF-D is transiently induced in brain endothelial cells at the injury site in the subacute phase. To investigate the biological significance of PDGF-D post-ischemic stroke regulation, its subacute expression was either downregulated using siRNA or upregulated using an active recombinant form. Attenuation of PDGF-D subacute induction exacerbates neuronal loss, impairs microvascular density, alters vascular permeability, and increases microvascular stalling. Increasing PDGF-D subacute bioavailability rescues neuronal survival and improves neurological recovery. PDGF-D subacute enhanced bioavailability promotes stable neovascularization of the injured tissue and improves brain perfusion. Notably, PDGF-D enhanced bioavailability improves pericyte association with brain endothelial cells. Cell-based assays using human brain pericyte and brain endothelial cells exposed to ischemia-like conditions were applied to investigate the underlying mechanisms. PDGF-D stimulation attenuates pericyte loss and fibrotic transition, while increasing the secretion of pro-angiogenic and vascular protective factors. Moreover, PDGF-D stimulates pericyte migration required for optimal endothelial coverage and promotes angiogenesis. Our study unravels new insights into PDGF-D contribution to neurovascular protection after ischemic stroke by rescuing the functions of pericytes.

项与 PDGFRβ 相关的新闻（医药）

2024-10-28

·生物探索

Cell Metab丨吕德官等揭示胶质母细胞瘤中调控表观转录的关键代谢途径

引言 N6-甲基腺苷（m6A）是最常见的真核mRNA内源性修饰之一，它广泛参与了mRNA的稳定性、剪接、转运和翻译等关键过程。m6A修饰通过影响代谢基因的稳定性和翻译，参与细胞代谢的调节。研究报道胶质母细胞瘤干细胞（Glioblastoma Stem Cells，GSCs）中血小板源性生长因子受体β （PDGFRβ）增加线粒体自噬相关基因（OPTN）m6A修饰和降解影响线粒体功能；表皮生长因子受体（EGFR）通过抑制谷胱甘肽合成酶（GCLM）m6A修饰促进GCLM表达和增加谷胱甘肽（GSH）合成【1】【2】。然而胶质干细胞中表观转录与关键代谢通路的相关作用以及靶向此相互作用的临床应用潜力仍不清楚。 2024年10月24日，匹兹堡大学医学中心Jeremy Rich教授团队在Cell Metabolism杂志上发表了题为Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2的论文。该研究揭示了胶质母细胞瘤干细胞中调控表观转录的关键代谢途径，探讨了靶向维持GSCs代谢和表观转录组网络的关键因子MDH2的治疗潜力，这为该致命性脑癌的治疗带来了新的希望。为了了解肿瘤层次结构中的全局代谢差异，作者对胶质瘤进行了全面、无偏差的稳态代谢谱分析，研究发现，与非干性胶质瘤母细胞细胞相比，负责胶质母细胞瘤生长和抗药性的胶质母细胞瘤干细胞依赖于苹果酸脱氢酶2（MDH2）的高活性来维持其恶性表型。靶向抑制MDH2，成功抑制了GSCs的增殖、自我更新能力，并在体内实验中抑制了肿瘤生长。在GSCs中MDH2的表达与RNA甲基化修饰，RNA代谢等生物过程最为相关，MDH2驱动的代谢变化影响了RNA m6A 甲基化。进一步的机制研究发现MDH2的抑制导致了一种名为α-酮戊二酸（αKG）的抑癌代谢物大量积累，而αKG在激活关键RNA调控酶（RNA去甲基化酶ALKBH5）中扮演重要角色。通过改变αKG的水平，研究团队成功扰乱了癌细胞的RNA m6A修饰功能，这种修饰是调控癌症相关基因稳定性和翻译的关键机制, 该修饰对于癌细胞维持干细胞状态及抵抗治疗至关重要。研究进一步揭示，抑制MDH2后一些关键肿瘤驱动基因的mRNA（如PDGFRβ）上的m6A修饰水平下降。尽管新的治疗手段为胶质瘤母细胞治疗提供了新希望，但是化疗仍然是肿瘤治疗包括胶质母细胞瘤治疗的最关键手段。当前针对胶质母细胞瘤的药物治疗种类和效果均有限，且治疗后的患者常常出现复发。其原因在于肿瘤干细胞的存在及其对化疗的耐药性。为了确定靶向MDH2对MDH2诱导的肿瘤的治疗潜力以及潜在药理学策略，作者分析了MDH2 基因表达与肿瘤药物反应相关性，发现MDH2的表达与多酪氨酸激酶（包括BCR-ABL、SRC）抑制剂达沙替尼的反应不良相关。研究探讨了MDH2抑制剂与多激酶抑制剂达沙替尼联合用药的治疗潜力。实验结果显示，这种联合治疗方法能显著增强肿瘤抑制效果，尤其在GSCs模型中，联合治疗大幅度延长了动物的生存期。这一联合打击策略为今后胶质母细胞瘤的治疗提供了全新的思路，具有重要的临床参考应用价值。总之，作者们的工作证明了胶质母细胞瘤干细胞对苹果酸-天冬氨酸穿梭和MDH2的高依赖性，以及MDH2对胶质母细胞瘤干细胞增殖和干性维持的重要性。MDH2通过α-酮戊二酸影响ALKBH5酶活性，继而影响靶基因的m6A修饰和稳定性，该发现揭示了MDH2是维持GSCs代谢和表观转录组网络的关键环节，为开发更为有效的靶向治疗方案铺平了道路。随着研究的深入，MDH2抑制剂有望与现有疗法结合，显著改善胶质母细胞瘤患者的治疗预后。未来这一研究成果进入临床试验，将为攻克这一侵袭性癌症带来全新治疗途径, 为胶质母细胞瘤患者带来治疗希望。模式图（Credit: Cell Metabolism）参考文献 1. Deguan Lv, Ryan C. Gimple, Cuiqing Zhong, Qiulian Wu, Kailin Yang, Briana C. Prager, Bhaskar Godugu, Zhixin Qiu, Linjie Zhao, Guoxin Zhang, Deobrat Dixit, Derrick Lee, Jia Z. Shen, Xiqing Li, Qi Xie, Xiuxing Wang, Sameer Agnihotri and Jeremy N. Rich. PDGF Signaling inhibits Mitophagy in Glioblastoma Stem Cells Through N6-Methyladenosine. Developmental Cell, 2022; S1534-5807(22)00349-5. doi: 10.1016/j.devcel.2022.05.007. 2. Deguan Lv, Cuiqing Zhong, Deobrat Dixit, Kailin Yang, Qiulian Wu, Bhaskar Godugu, Briana C Prager, Guofeng Zhao, Xiuxing Wang, Qi Xie, Shideng Bao, Chuan He, Dieter Henrik Heiland, Michael G Rosenfeld, Jeremy N Rich. EGFR promotes ALKBH5 nuclear retention to attenuate N6-methyladenosine and protect against ferroptosis in glioblastoma. Mol Cell. 2023;83(23):4334-4351.e7. doi: 10.1016/j.molcel.2023.10.025. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cmet.2024.09.014 责编|探索君排版|探索君来源|BioArt End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

信使RNA

2024-10-26

·精准药物

【Chemical Science】浙江大学侯廷军等：基于片段的分子生成模型FragGen

基于三维结构的分子生成是生成式人工智能在药物发现中的成功应用之一。早期出现的基于原子的分子生成模型如LiGAN、Pkt2Mol、DiffBP和ResGen等，输出的分子通常具有较好的对接分数，但同时也普遍存在两个问题：一是生成的分子构象经常出现扭曲或偏离口袋（图-1 GraphBP和DiffBP）；二是倾向于生成大的并环结构来填充口袋（图-1PktMol和ResGen）。虽然这样的结构可能会与靶蛋白产生更强的相互作用，但是复杂的结构往往不利于合成且易导致毒性。基于片段的分子生成以可合成的分子片段为基础，为提高生成分子的可合成性提供了方向，但是现有的基于片段的分子生成模型如FLAG，在生成具有合理几何形状的分子方面表现不佳（图-1）。因此，在基于结构的药物设计中，迫切需要一种可靠的基于片段的分子生成模型。浙江大学侯廷军课题组联合中国科学技术大学和蒙特利尔学习算法研究所在Chemical Science上发表文章“FragGen: Towards 3D Geometry Reliable Fragment-based Molecular Generation[1]”。基于现有分子生成方法的优缺点，作者提出了一种组合策略并基于该策略开发了基于片段的分子生成方法FragGen，该方法显著提高了生成分子的结构质量和可合成性，克服了以前模型的主要局限性。FragGen已经成功地应用于现实场景并在nM水平上设计了II型激酶抑制剂。图-1 不同方法生成的分子部分列举。为解决生成分子几何结构不合理的问题，作者总结了目前在分子生成领域常用的六种几何结构处理方法（图-2）：1）内部坐标法，在预测键长、键角和二面角之前先确定所有原子的连接顺序，但基于复杂的蛋白质口袋环境生成合理的拓扑顺序是困难的，且该方法主要关注局部的原子连接信息，忽视了分子整体的空间结构和对称性。2）笛卡尔坐标法，通过对三维坐标进行概率学习来预测原子坐标，由于没有考虑原子间的局部化学结构约束，每次预测误差的累积会导致最终几何结构不合理。3）相对矢量法，通过预测原子间的坐标向量差将自由度限制在键长上，减少需要预测的信息量，降低预测误差对整体分子几何结构的影响。4）GeomGNN，利用等变图神经网络学习原子之间的力并用于更新原子坐标，不仅训练和推理过程简单直接且能够高效生成符合全局几何特性的分子，但在实现局部几何结构的准确性方面仍存在局限性。5）GeomOPT，通过模拟分子内部的力场相互作用来预测原子的位置，理论上可以避免生成局部结构不合理的分子模型，但是为了找到合理的分子结构需要进行大量的迭代计算，在优化过程中还有可能陷入局部能量最小值，从而导致最终分子构象的扭曲。6）距离几何法，通过模拟原子间的距离来避免神经网络设计中的等变性需求，减少了模型构建的复杂性，但自由度过剩使得无法从距离矩阵中确定唯一的三维坐标，因此常导致构象扭曲。图-2 不同几何处理方法的工作流程、面临的挑战、应用举例和其他模型信息（MG：分子生成，S-MG：基于结构的分子生成，CG：构象生成和S-CG：基于结构的构象生成，即分子对接）。基于以上各种方法的优缺点，作者提出了一种用于基于片段的分子生成的组合策略（图-3）：首先通过相互作用学习模块分析蛋白质口袋中的几何特征和关键位点，从片段库中挑选合适的初始片段并将其放在口袋合适的位置，接着利用相对矢量法检测潜在子口袋以确定后续片段组装的合适位置，然后预测下一个片段的类型并使用GeomOPT通过力场优化方法调整片段之间的键长、键角和相对位置，确保连接部分的几何结构合理性，同时结合化学知识如杂化轨道理论对生成的分子碎片进行初始化以保证其遵循化学规则，最后使用vonMises损失函数预测分子片段之间的二面角，确保二面角的旋转符合分子整体的几何约束，并使生成的分子片段能在三维空间中合理排布。图-3 FragGen生成分子的工作流程。作者引入了两个新的指标来定量评估生成分子的几何合理性：松弛能量（RelaxE）和优化均方根偏差（OptRMSD）。即计算对生成分子进行力场优化后释放的能量（图-4A）和RMSD。由于大的芳香族体系不易产生构象变化，因此OptRMSD在多环化合物中的值一般较小，因此ResGen与FragGen生成化合物的OptRMSD值虽然相似，但FragGen生成化合物释放的能量却更低（图-4B-D），展现了其在生成合理几何构象方面的优势。对于FLAG这种易生成扭曲构象的模型，在两个指标上的结果均不理想（图-4B）。图-4 （A）生成和优化后分子几何形状在能量景观图中的位置；（B-D）三种方法中三个例子的RelaxE和OptRMSD值。作者评估和比较了FragGen和其他分子生成方法在CrossDock基准测试集上的性能，结果表明FragGen在VinaScore上的表现优于其他所有方法，在可合成性方面，当其他方法的SA值还在0.3到0.6范围内波动时，FragGen的SA值已经稳定在0.7以上。为证明FragGen在现实场景中的适用性，作者评估了该方法在几个经过充分研究的药物靶标上的性能。结果表明FragGen生成分子与Active数据集（实验验证的化合物）中分子的VinaScore分布较为接近（图-5A），且在VinaScore相似的情况下，FragGen在生成可合成性较好的分子方面的表现远优于ResGen（图-5B）。图-5 （A）FragGen和FLAG在AKT1、CDK2和JAK2三个靶点上生成分子的结合能力（VinaScore）分布；（B）对比可视化前5个分子与靶标的结合能力和可合成性。最后，参考PDGFRβ靶点基于I型抑制剂信息设计II型抑制剂的思路，作者使用FragGen设计了激酶LTK的II型抑制剂并进行了湿实验验证。首先基于间变性淋巴瘤激酶ALK建立LTKDFG-out同源模型，接着将已报道的ALKI型抑制剂对接到LTK模型中并提取与I型口袋核心区域有紧密相互作用的分子片段，然后基于该分子片段进行分子生成。在10分钟内，FragGen生成了97种分子，以氢键供体数< 5，氢键受体数< 10，2 < LogP < 5和可旋转键数< 10为条件过滤后获得10个分子，根据可合成性选择其中的三个进行了湿实验验证分析。其中化合物Darma-1具有最好的活性，IC50值为75.1nM（图-6A）。对结合模式的分析表明Darma-1与LTK的II型口袋形成了全面的物理相互作用（图-6B-D），包括与ASP-155、LYS-35和GLU-52形成的氢键相互作用和其他疏水相互作用。这表明FragGen能够生成在三维空间中形状和排列合理且能够与蛋白质活性位点正确结合的分子结构。图-6 （A）FragGen设计的三个化合物的结构及其对Ba/F3-CLIP1-LTK细胞的抑制活性（IC50）；（B）Darma-1结合构象；（C）三维蛋白-配体相互作用分析；（D）二维蛋白-配体相互作用分析（绿色表示疏水相互作用，蓝色表示氢键相互作用）。小结：作为一种基于片段的分子生成方法，FragGen生成的分子不仅在结合亲合力方面与目前最优的方法表现相当，而且在可合成性方面也表现出较大的优势，对II型LTK抑制剂的成功设计表明了FragGen在实际应用中的潜力。但是FragGen的几何处理策略较为复杂，在复杂体系中进行多次迭代优化时，可能需要大量计算资源，这在应用于大规模片段库筛选时可能会成为瓶颈。此外FragGen在其他靶点上的应用仍需进一步验证。参考文献： [1] Yu, M.; Zeng, Y.; Wang, M.; Hua, C.; Cui, S.; Pan, P.; Hsieh, C.-Y.; Hou, T.; Zhang, O.; Huang, Y.; Chen, S.; Zhang, X.; Lin, H.; Wu, Z.; Zhao, H.; Zhang, Z.; Kang, Y. FragGen: Towards 3D Geometry Reliable Fragment-based Molecular Generation. Chem. Sci. 2024 Oct 16. 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

2024-10-17

·BioSpace

AB Science provides an update on the application for conditional marketing authorisation of masitinib in ALS

PRESS RELEASE AB SCIENCE PROVIDES AN UPDATE ON THE APPLICATION FOR CONDITIONAL MARKETING AUTHORISATION OF MASITINIB IN THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS Paris, 17 October, 2024, 7.30pm CET AB Science SA (Euronext - FR0010557264 - AB) today announces that the European Medicines Agency (EMA) confirmed a negative opinion for the conditional marketing authorization of masitinib in the treatment of amyotrophic lateral sclerosis (ALS), following a vote adopted during the Committee for Medicinal Products for Human Use (CHMP) meeting on 14-17 October 2024. The Conditional Marketing Authorization of masitinib had been under review by the CHMP in response to the company’s request for a re-examination of the negative opinion issued in June 2024. Despite the difficulty of a conditional marketing authorization in ALS, AB Science had asked for a re-examination first and foremost considering the urgent need for patients to have early access to a promising treatment and the clinical data obtained from the first study AB10015, showing an increase in median overall survival of + 6 months (p= 0.0761) in the primary analysis population of Normal progressors, and a significant + 12 months survival benefit (p=0.0192) in a subgroup defined as patients prior to any complete loss of function (i.e. excluding patient with an ALSFRS-R score of 0 in any of the 12 items of the scale). A Scientific Advisory Group – Neurology (SAG-N) was conveyed for the first time, as part of the re-examination procedure. Importantly, the SAG-N experts agreed with the categorization approach to distinguish between Normal and Fast Progressors (and with the 1.1 points per month ALSFRS decline from onset as cut-off), if properly pre-specified. This opinion supports the design of the confirmatory study of masitinib in ALS, as the same dichotomization and the same cut-off have been pre-specified for the confirmatory study. The phase 2B/3 study AB10015 is considered hypothesis generating but not sufficient as a single pivotal study to support a marketing authorization. Separately, Health Canada recently informed AB Science that key analyses presented for the reconsideration submitted in May 2024 [1], have been considered as new data, rather than re-analyses of existing data. Considering that Health Canada guideline prevent the use of new data as part of the re-examination procedure, AB Science has decided to notify Health Canada it will not pursue the reconsideration. Health Canada has offered the possibility to submit a new application to resolve this issue. Alain Moussy, CEO and co-founder of AB Science said “ We are thankful to the patients and physicians that supported the re-examination process as part of the EMA review. We did all these efforts for the patients. We are convinced that masitinib is a promising drug when we see patients from the study surviving with the drugs for more than 10 years in our compassionate use program. Now AB Science objective is to focus on the confirmatory phase 3 program of masitinib in ALS to reach full approval ”. References [1] AB Science press release dated 3 April 2024 About AB Science Founded in 2001, AB Science is a pharmaceutical company specializing in the research, development and commercialization of protein kinase inhibitors (PKIs), a class of targeted proteins whose action are key in signaling pathways within cells. Our programs target only diseases with high unmet medical needs, often lethal with short term survival or rare or refractory to previous line of treatment. AB Science has developed a proprietary portfolio of molecules and the Company’s lead compound, masitinib, has already been registered for veterinary medicine and is developed in human medicine in oncology, neurological diseases, inflammatory diseases and viral diseases. The company is headquartered in Paris, France, and listed on Euronext Paris (ticker: AB). Further information is available on AB Science’s website: . Forward-looking Statements - AB Science This press release contains forward-looking statements. These statements are not historical facts. These statements include projections and estimates as well as the assumptions on which they are based, statements based on projects, objectives, intentions and expectations regarding financial results, events, operations, future services, product development and their potential or future performance. These forward-looking statements can often be identified by the words “expect”, “anticipate”, “believe”, “intend”, “estimate” or “plan” as well as other similar terms. While AB Science believes these forward-looking statements are reasonable, investors are cautioned that these forward-looking statements are subject to numerous risks and uncertainties that are difficult to predict and generally beyond the control of AB Science and which may imply that results and actual events significantly differ from those expressed, induced or anticipated in the forward-looking information and statements. These risks and uncertainties include the uncertainties related to product development of the Company which may not be successful or to the marketing authorizations granted by competent authorities or, more generally, any factors that may affect marketing capacity of the products developed by AB Science, as well as those developed or identified in the public documents published by AB Science. AB Science disclaims any obligation or undertaking to update the forward-looking information and statements, subject to the applicable regulations, in particular articles 223-1 et seq. of the AMF General Regulations. For additional information, please contact: AB Science Financial Communication & Media Relations investors@ab-science.com Attachment CP ALS REGUL EMA VENG VF

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