BACKGROUND AND OBJECTIVES Inhibition of Abelson (Abl) tyrosine kinase as a therapeutic target has been gaining attention in neurodegeneration. Post-mortem Alzheimer's and Parkinson's disease brains show that the levels of several other tyrosine kinases, including Discoidin Domain Receptors (DDR1/2) are elevated. Knockdown of these tyrosine kinases with shRNA reduces neurotoxic proteins, including alpha-synuclein, beta-amyloid and tau. METHODS Direct profiling of the pharmacokinetics of multi-kinase inhibitors Nilotinib, Bosutinib, Bafetinib, Radotinib and LCB-03-0110 shows differential levels of brain penetration but the ability of these agents to reduce toxic proteins is independent of brain concentration and selectivity to Abl. RESULTS Our results indicate that the effective dose of Nilotinib has the lowest plasma:brain ratio (1%) followed by Bosutinib and Radotinib (5%), Bafetinib (12%) and LCB-03-0110 (12%). However, similar doses of multi-kinase Abl/DDR inhibitor Nilotinib, DDR/Src inhibitor LCB-03-0110 and Abl/Src inhibitor Bosutinib were much more effective than the more selective Abl inhibitors Radotinib and Bafetinib. Taken together, these data suggest that a multi-kinase target that includes Abl and other tyrosine kinases (DDRs, and Src) may offer more advantages alleviating neurodegenerative pathologies than the absolute CNS drug concentration and selectivity to Abl. CONCLUSION DDRs and Src are other potential co-targets with Abl in neurodegeneration.

中文翻译：

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多激酶Abl / DDR / Src抑制作用可抑制神经变性中的酪氨酸激酶抑制作用。

背景和目的抑制Abelson（Abl）酪氨酸激酶作为治疗靶点已引起神经变性的关注。验后的阿尔茨海默氏病和帕金森氏病大脑显示，包括盘状蛋白结构域受体（DDR1 / 2）在内的其他几种酪氨酸激酶的水平也在升高。用shRNA敲低这些酪氨酸激酶可减少神经毒性蛋白，包括α-突触核蛋白，β-淀粉样蛋白和tau蛋白。方法直接分析多种激酶抑制剂Nilotinib，Bosutinib，Bafetinib，Radotinib和LCB-03-0110的药代动力学显示出不同的脑渗透水平，但这些药物减少毒性蛋白的能力与脑部浓度和对Abl的选择性无关。结果我们的结果表明尼洛替尼的有效剂量具有最低的血浆：大脑比例（1％），其次是波舒替尼和拉托替尼（5％），巴非替尼（12％）和LCB-03-0110（12％）。但是，类似剂量的多激酶Abl / DDR抑制剂Nilotinib，DDR / Src抑制剂LCB-03-0110和Abl / Src抑制剂Bosutinib比选择性更高的Abl抑制剂Radotinib和Bafetinib更为有效。综上所述，这些数据表明，与绝对CNS药物浓度和对Abl的选择性相比，包括Abl和其他酪氨酸激酶（DDRs和Src）的多激酶靶标在缓解神经退行性病变方面可能具有更多优势。结论DDR和Src是神经退行性变中与Abl潜在的共同靶标。DDR / Src抑制剂LCB-03-0110和Abl / Src抑制剂博舒替尼比更具选择性的Abl抑制剂Radotinib和Bafetinib更为有效。综上所述，这些数据表明，与绝对CNS药物浓度和对Abl的选择性相比，包括Abl和其他酪氨酸激酶（DDRs和Src）的多激酶靶标在缓解神经退行性病变方面可能具有更多优势。结论DDR和Src是Abl在神经退行性变中的其他潜在共同靶标。DDR / Src抑制剂LCB-03-0110和Abl / Src抑制剂博舒替尼比更具选择性的Abl抑制剂Radotinib和Bafetinib更为有效。综上所述，这些数据表明，与绝对CNS药物浓度和对Abl的选择性相比，包括Abl和其他酪氨酸激酶（DDRs和Src）的多激酶靶标在缓解神经退行性病变方面可能具有更多优势。结论DDR和Src是Abl在神经退行性变中的其他潜在共同靶标。