Anle138b is a low polymer aggregation inhibitor with low toxicity, high oral bioavailability, and the ability to penetrate the blood-brain barrier. It can prevent the formation of pathological aggregates of prion protein (PrPSc) and α-synuclein [1]. Protein aggregates (also known as prion-like transmission) transfer between cells in the brain, leading to neurodegenerative diseases. Polymer aggregates are considered key neurotoxins [2]. Anle138b can be used in the research of neurodegenerative diseases (such as prion diseases, Parkinson's disease, etc.) [3-4].
In vitro, Anle138b (7μM; 16h) treatment reduced the formation of mHTT aggregates in human neural precursor cells (NPCs) and improved neurotoxicity [5]. Anle138b (10 and 30mM; 48h) treatment significantly changed the cell morphology of human melanoma cell lines and inhibited their proliferation, disrupted their plasma membranes and mitochondrial membrane potential, and led to autophagy dysregulation [6].
In vivo, Anle138b (2g/kg for 7 days diet) significantly changed the morphology of tumor tissues in WM983-B (MGP) human melanoma xenograft mice through oral treatment, and increased the number of LC3-positive cells [6]. Anle138b (0.6and 2 g/kg for 4-month diet) significantly reduced the α-synuclein oligomers and neuroglial cytoplasmic inclusions in PLP-hαSyn mice and protected dopaminergic neurons from death and reduced the activation of microglia in the substantia nigra [7].
References:
[1] Wagner J, Ryazanov S, Leonov A, et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease[J]. Acta neuropathologica, 2013, 125(6): 795-813.
[2] Sidoryk-Węgrzynowicz M, Adamiak K, Strużyńska L. Targeting protein misfolding and aggregation as a therapeutic perspective in neurodegenerative disorders[J]. International Journal of Molecular Sciences, 2024, 25(22): 12448.
[3] Martinez Hernandez A, et al. The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology. EMBO Mol Med. 2018;10(1):32-47.
[4] Levin J, Sing N, Melbourne S, et al. Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial[J]. EBioMedicine, 2022, 80.
[5] da Silva Padilha M, Koyuncu S, Chabanis E, et al. Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington’s disease[J]. bioRxiv, 2025: 2025.03. 11.642540.
[6] Turriani E, Lázaro D F, Ryazanov S, et al. Treatment with diphenyl–pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death[J]. Proceedings of the National Academy of Sciences, 2017, 114(25): E4971-E4977.
[7] Heras-Garvin A, Weckbecker D, Ryazanov S, et al. Anle138b modulates α-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy. Mov Disord. 2019;34(2):255-263.
Anle138b是一种毒性低，口服生物利用度高并能穿透血脑屏障的低聚物聚集抑制剂，能够阻止朊蛋白（PrPSc）和α-突触核蛋白（α-syn）的病理性聚集物的形成 [1]。蛋白质聚集物（也被称为朊病毒样传播）会在脑内细胞之间进行转移，从而导致神经退行性病变。低聚物聚集体被认为是关键的神经毒剂 [2]。Anle138b可用于神经退行性疾病（如朊病毒、帕金森氏病等）的治疗研究 [3-4]。
在体外，Anle138b（7μM; 16h）处理减少了人类神经前体细胞（NPCs）中mHTT聚集体的形成并改善了神经毒性 [5]。Anle138b（10 and 30mM; 48h）处理显著改变了人黑色素瘤细胞系的细胞形态并抑制其增殖，破坏其质膜和线粒体膜电位，并且导致自噬失调 [6]。
在体内，Anle138b（2g/kg for 7 days diet）通过口服治疗显著改变了WM983-B（MGP）人黑色素瘤异种移植小鼠中肿瘤组织的形态，并增加了LC3阳性细胞的数量 [6]。Anle138b（0.6 and 2g/kg for 4 months diet）通过口服治疗显著减少了PLP-hαSyn小鼠体内的α-突触核蛋白寡聚体和神经胶质细胞质包裹体，保护多巴胺能神经元存活并减少黑质中小胶质细胞的活化 [7]。