Multikinase Abl/DDR/Src Inhibition Produces Optimal Effects for Tyrosine Kinase Inhibition in Neurodegeneration

Abstract

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. Electronic supplementary material The online version of this article (10.1007/s40268-019-0266-z) contains supplementary material, which is available to authorized users.

Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease

“…[4][5][6] However, nilotinib more potently inhibits DDR1 (IC 50 = 1-8 nM). [4][5][6][7][8] The concentration of CSF nilotinib in 150 mg and 300 mg nilotinib-treated groups (3.46 nM and 4.7 nM, respectively) exceeds the IC 50 required to inhibit DDR1. Therefore, nilotinib achieves sufficient CSF levels to what would potentially inhibit DDR1, and alter disease biomarkers.…”

“…3 Nilotinib (Tasigna, AMN107; Novartis, Switzerland) is a tyrosine kinase inhibitor that preferentially targets discoidin domain receptors (DDRs) [4][5][6][7][8] and effectively reduces misfolded proteins in animal models of neurodegeneration. 7,[9][10][11][12][13][14][15][16] Nilotinib also targets the nonreceptor tyrosine kinase Abelson [4][5][6] and is FDAapproved for the treatment of Philadelphia chromosome positive chronic myeloid leukemia (CML) at oral doses of 300 mg twice daily. [4][5][6] Low doses of nilotinib penetrate the bloodbrain barrier and promote the degradation of Aβ and tau in animal models of neurodegeneration.…”

“…7,[9][10][11][12][13][14][15][16] Clinical studies indicate that nilotinib enters the central nervous system (CNS; peak plasma concentration [C max ] 2-4 nM in cerebrospinal fluid [CSF]), increases dopamine turnover, and reduces CSF tau, independent of Abelson inhibition [17][18][19] -further suggesting that nilotinib effects may be mediated by DDR1 inhibition (half-maximal inhibitory concentration [IC 50 ] 1-8 nM). 8,20,21 The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of nilotinib in participants with mild to moderate dementia due to AD. Secondary objectives included evaluation of the effect of nilotinib on amyloid biomarkers-CSF Aβ42 and Aβ40 and CNS amyloid burden (Florbetaben positron emission tomography [PET]), and markers of tauopathy and neurodegeneration-CSF phospho-tau (ptau-181), total tau, and hippocampal volume (magnetic resonance imaging [MRI]).…”

Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-Src Tyrosine Kinase

“…It is the prototype of a larger family, comprising at least nine members, most of them with little activity in normal cells in the absence of stimulatory signals (2). Src kinases have been suggested to be involved in the exacerbation of neurodegenerative pathologies, whereas their inhibition would diminish microgliosis and mitigate inflammation, findings that are in line with experimental effects seen for non-specific src inhibitors such as bosutinib or LCB-03-0110 (3). Inhibition of src kinases has been suggested by non-clinical evidence as a potential method of therapy for the pulmonary vascular remodeling and right ventricular hypertrophy in pulmonary hypertension (4), although several reports indicate that dual Abl/src inhibitor dasatinib may actually induce pulmonary hypertension (5)(6)(7); it was more recently suggested that this dasatinib effect may in fact be independent of the src inhibition (7).…”

A new avenue for treating Parkinson's disease targeted at aggrephagy modulation and neuroinflammation: Insights from in vitro and animal studies

“…Recent evidence suggests the involvement of c-Abl TK in the pathogenesis of PD through Parkin inactivation, a-synuclein aggregation, and impaired autophagy of toxic elements [7]. Inhibition of this kinase activity has been suggested as a potential target in the treatment of PD [7,8]. Indeed, Suresh and colleagues [5] found that PD180970 clears toxic protein aggregates and exerts cytoprotection against a-synuclein toxicity in an autophagy-dependent manner through increased autophagy flux and augmented autophagosome numbers in vitro.…”