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FDA-Approved Kinase Inhibitors in Trials for Neurological Disorders: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Austin Lui.

The United States Food and Drug Administration (US FDA) has so far approved 74 kinase inhibitors, with numerous other kinase inhibitors in clinical trials, mostly for the treatment of cancers. In contrast, there are dire unmet needs of FDA-approved drugs for neurological treatments, such as Alzheimer’s disease (AD), intracerebral hemorrhage (ICH), ischemic stroke (IS), traumatic brain injury (TBI), and others.

  • aberrant cell cycle disease
  • cancers
  • neurological disorders
  • kinase inhibitors

1. FDA-Approved Kinase Inhibitors in Clinical Trials for Neurological Disorders

Many of the FDA-approved kinase inhibitors have been tested in clinical and preclinical trials for neurological disorders, though none of them have been approved by the FDA for neurological treatment. In terms of clinical trials, Baricitinib, a JAK inhibitor, is being studied in a phase II trial (NCT03921554) along with a phase II and III trial (NCT04517253), for efficacy and safety in Aicardi–Goutieres Syndrome, an inherited encephalopathy that affects infants and usually results in severe mental and physical disabilities.
Bosutinib, an inhibitor of Src and Bcr-Abl, is and has been investigated in clinical trials for different neurodegenerative disorders. There is a phase I trial (NCT04744532) studying the safety and tolerability of bosutinib for amyotrophic lateral sclerosis (ALS), a progressive neurological disease leading to loss of muscle control. The safety, tolerability, and clinical outcomes of bosutinib on patients with dementia with Lewy bodies has also been studied in a completed phase 2 trial (NCT03888222). In preclinical studies, it has been found that bosutinib reduces levels of alpha-synuclein, tau, and beta-amyloid in the CNS, and improves motor and cognitive behavior in animal models [38,39,40][1][2][3]. Bosutinib was also found to promote autophagy and clear protein aggregates in neurons [41,42][4][5]. There is also an ongoing phase I trial (NCT02921477) studying the safety and tolerability of bosutinib for mild cognitive impairment (MCI) and dementia.
Cobimetinib, an MEK inhibitor, has been studied in a phase 2 trial (NCT04079179) studying its safety and efficacy in histiocytic disorders, which can lead to neurodegeneration. Dasatinib, an inhibitor of Src, Bcr-Abl, Kit, EGFR, PDGFR, and EPH (EphA2), has been studied in multiple clinical trials examining its effectiveness in treating AD and mild cognitive impairment. Particularly, in four clinical trials (NCT04063124—phase I and II, NCT04785300—phase I and II, NCT04685590- phase II, NCT05422885—phase I/II), the safety, feasibility, and efficacy of dasatinib and quercetin, a flavonoid known to have antioxidant and anti-inflammatory effects, are being assessed.
Everolimus, an inhibitor of mTOR and FKBP, has been extensively evaluated in clinical trials studying different acute brain injury disorders, neurodegenerative disorders, and neurodevelopmental disorders. A phase II trial (NCT03198949) studying the safety and anti-epileptic efficacy of everolimus in patients with Epilepsy and focal cortical dysplasia II, who have failed more than two antiepileptic drugs and surgery, has been recently completed. Everolimus has been shown in animal models to protect seizure-induced brain injury and reduce neuroinflammation associated with seizures [43,44][6][7]. A phase II trial (NCT00857259) evaluating the safety and efficacy of everolimus with or without ranibizumab in patients with neovascular age-related macular degeneration, a neurodegenerative disorder that results in a loss of central vision, is currently in progress. Additionally, in a phase I and II trial (NCT02991807), researchers studied whether everolimus can improve neurocognitive outcomes in patients with hamartoma tumor syndrome caused by a PTEN germline mutation. There are also multiple studies (NCT02962414, NCT01730209, NCT01070316, NCT01713946, NCT02451696, NCT01954693, NCT01929642, and NCT012899-12) evaluating the safety and efficacy of everolimus in patients with tuberous sclerosis complex, which is often associated with refractory seizures, cognitive disabilities, autism, focal cortical dysplasia, other neurocognitive problems, and self-injury. Lastly, there is a phase II trial that studied the safety and efficacy of everolimus in patients with seizures who have Sturge–Weber syndrome, a rare disease in which tumors form in the brain (NCT01997255).
Imatinib, a Bcr-Abl, Kit and PDGFR inhibitor, has been studied in several acute brain injury and neurodegenerative disorders. In a phase III trial (NCT03639922), imatinib was studied in ischemic stroke patients to determine whether there was improvement in functional outcomes. Imatinib, administered for 6 days, was added to conventional stroke therapy and started within 8 days of the onset of stroke. Additionally, in a phase II trial (NCT02363361), the safety, uptake, and tolerability of imatinib is being studied in patients with cervical SCI. A phase II trial (NCT03674099) is currently testing imatinib as a novel therapy for multiple sclerosis, comparing its efficacy to methylprednisolone, the standard of care drug for multiple sclerosis relapses. Lastly, imatinib had been studied in a phase I trial (NCT00403156), examining choroidal neovascularization, although this study has been withdrawn.
Nilotinib is a kinase inhibitor that inhibits the activity of Bcr-Abl, PDGFR and DDR1. It has been studied in several neurodegenerative diseases in clinical trials. In a phase I study, nilotinib (NCT03764215) was administered to patients with Huntington disease. Biomarkers, such as phosphorylated tau levels, and functional outcomes were assessed. In an ongoing phase II study (NCT04002674), the use of nilotinib in patients with dementia with Lewy bodies is being studied, particularly on the pharmacokinetics, tolerability, biomarkers, and safety of use. In a phase II study (NCT02947893), the efficacy of nilotinib in AD was studied. Specifically, the effects of nilotinib on cell death was detected with cell markers, and the amyloid concentrations in the brain were assessed with PET scans. Also, a recent phase III clinical trial (NCT05143528) is currently studying the safety and efficacy of nilotinib in patients with early AD using two different dosages. There are also three studies that examined the effects of nilotinib in patients with Parkinson’s disease (NCT02954978, NCT02281474, NCT03205488). In a phase II trial (NCT03932669), the efficacy and adverse events of nilotinib are being studied in patients with spinocerebellar ataxia. In particular, improvement in daily living performance and cerebellar functions are being assessed.
Pazopanib inhibits the activities of VEGFR 1/2/3, PDGFR α/β, FGFR 1/3, Kit, Lck, Fms, and Itk. In terms of neurological disease settings, it is studied mainly in macular degeneration (NCT00659555, NCT01154062, NCT00612456, NCT01072214, NCT00463320, NCT01362348, NCT01134055, NCT01051700, and NCT00733304). Regorafenib, a VEGF kinase inhibitor, was studied in neovascular age-related macular degeneration. After successfully passing phase I clinical trials, (NCT02222207), phase IIa trials were terminated after the results were less effective than the current gold standard treatment [45][8].
Sirolimus, an mTOR inhibitor initially used as an immunosuppressant in kidney transplants, has been repurposed in a multitude of neurological and psychiatric clinical trials, including cerebral aneurysms (NCT04141020), epilepsy (NCT03646240), Alzheimer’s disease (NCT04629495 and NCT04200911), frontotemporal dementia (NCT04408625), amyotrophic lateral sclerosis (NCT03359538), Parkinson’s disease (NCT04127578), age-related macular degeneration (NCT01445548, NCT00766649, NCT00712491, NCT02357342, NCT02732899, NCT00766337, and NCT00304954), multiple sclerosis (NCT00095329), geographic atrophy associated with age-related macular degeneration (NCT01675947), multiple system atrophy (NCT03589976), Sturge–Weber syndrome (NCT03047980 and NCT02080624), lysosomal diseases (NCT03952637), Leigh syndrome (NCT03747328), tuberous sclerosis complex (NCT04595513, NCT01929642, and NCT05104983), Gaucher disease type 2 (NCT04411654), diabetic retinopathy (NCT00711490), diabetic macular edema (NCT00656643 and NCT00401115), alcohol use disorder (NCT03732248), smoking cessation (NCT04161144), depression (NCT02487485), and stroke prevention (NCT04948749).

2. FDA-Approved Kinase Inhibitors in Preclinical Trials for Neurological Disorders

While there have been 16 FDA-approved kinase inhibitors in clinical trials for neurological disorders, there are numerous preclinical studies of FDA-approved kinase inhibitors evaluating their effects on neurological disorders. Abemaciclib has been studied in preclinical models for the treatment of motor neuron degeneration [46][9] and post-traumatic stress disorder [47][10]. Afatinib has been tested in preclinical models for the treatment of oxygen/glucose deprivation-induced neuroinflammation [48][11], multiple sclerosis [49][12], autoimmune CNS inflammation [49][12], and nicotine dependance [50][13]. Axitinib has been tested for treatment of AD [51][14]. Alectinib has been tested for the potential treatment of binge drinking [52,53][15][16]. Baricitinib has been tested in preclinical models for the potential treatment of neurocognitive disorders induced by HIV [54][17], encephalitis [55[18][19],56], multiple sclerosis [56][19], hypersensitivity in Down syndrome [57][20], acute spinal cord injury [58][21], Hutchinson–Gilford progeria [59][22], and AD [60][23]. Binimetinib has been shown in a preclinical study to be a potential treatment for some forms of AD [61][24]. Bosutinib has been tested for the potential treatment of intracerebral hemorrhage [62][25], cerebral ischemia [63][26], α-synucleinopathies and tauopathies in neurodegeneration [40[3][4],41], Parkinson’s disease [38[1][5][27],42,64], TDP-43 pathology [65][28], SIN1-mediated neurotoxicity [66][29], and botulinum neurotoxins [67][30]. Cabozantinib has been tested for the potential treatment of Rett syndrome [68][31] and AD [69][32].
Crizotinib has been tested for the potential treatment of Parkinson’s disease [70][33], AD [71][34], persistent pain [72][35], Toxoplasma gondii (can result in symptoms of congenital neurological and meningoencephalitis) [73][36], and craniosynostosis associated with Saethre–Chotzen syndrome [74][37]. Dabrafenib has been tested for the potential treatment of ischemic brain injury [75][38], spinal cord injury [76][39], Parkinson’s diseases [77[40][41],78], and ataxia caused by neurohistiocytosis of the cerebellum [79][42]. Dasatinib has been tested for the potential treatment of traumatic brain injury [80][43], lipopolysaccharide-induced neuroinflammation [81][44], kainic acid-induced neuroinflammation [82][45], glaucoma [83][46], tau-associated pathology [84][47], multiple sclerosis [85][48], amyotrophic lateral sclerosis [86[49][50][51],87,88], Parkinson’s disease [87][50], age-related blood brain barrier dysfunction [89][52], age-related cognitive dysfunction [89[52][53],90], obesity-induced anxiety [91][54], chronic unpredictable stress-induced cognitive deficits [92][55], fetal alcohol syndrome [93][56], and botulinum neurotoxins [67][30]. Erlotinib has been tested for the potential treatment of nerve fiber injury [94][57], intracranial aneurysm formation [95][58], amyotrophic lateral sclerosis [96][59], diabetic peripheral neuropathy [97[60][61],98], and amyloid-β-induced memory loss [99][62].
Everolimus has been tested for the potential treatment of encephalopathy of prematurity [100][63], atherosclerosis-associated brain hypoxia [101][64], ischemic stroke [102[65][66][67],103,104], Alzheimer’s disease [105[68][69],106], Huntington disease [107[70][71],108], vascular dementia [109][72], lipopolysaccharide-induced neuroinflammation [110][73], insulin dysfunction-related cognitive dysfunction [111][74], glutamate-induced neurotoxicity [112][75], Guillain–Barre syndrome [113][76], multiple sclerosis [114][77], tuberous sclerosis complex-associated autism-like social deficits [115[78][79],116], and Lafora disease [117][80]. Fedratinib has been tested for the potential treatment of ischemic stroke [118][81], intracerebral hemorrhage [119][82], Wernicke’s encephalopathy [120[83][84],121], and Alzheimer’s disease [122][85]. Gefitinib has been tested for the potential treatment of spinal cord injury [123][86], amyloid-β-induced memory loss [99][62], schizophrenia [124][87], Streptococcus pneumoniae meningitis [125][88], and Toxoplasma gondii (can result in symptoms of congenital neurological and meningoencephalitis) [73,126][36][89].
Ibrutinib has been tested for the potential treatment of ischemic stroke [127[90][91],128], spinal cord injury [129,130][92][93], age-related cognitive deterioration [131][94], Alzheimer’s disease [132[95][96],133], lipopolysaccharide-induced neuroinflammation [134][97], anxiogenic behavior [135][98], depression [136,137][99][100], and cocaine use disorder [138][101]. Imatinib has been tested for the potential treatment of subarachnoid hemorrhage [139[102][103][104][105][106][107],140,141,142,143,144], intracerebral hemorrhage [145[108][109][110][111],146,147,148], cerebral small vessel disease [149][112], traumatic brain injury-induced seizures [150][113], seizures [150[113][114],151], traumatic brain injury [152][115], ischemia reperfusion-induced cerebral injury [153[116][117],154], Alzheimer’s disease [155[118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133],156,157,158,159,160,161,162,163,164,165,166,167,168,169,170], Parkinson’s disease [171[134][135][136][137],172,173,174], prion diseases [175[138][139][140][141],176,177,178], amyotrophic lateral sclerosis [179][142], Huntington’s diseases [180][143], cerebral malaria [181][144], hypoxic ventilatory depression [182][145], Niemann–Pick type C disease [183][146], Niemann–Pick type A disease [184][147], Gaucher disease [185][148], simian human immunodeficiency virus encephalitis [186][149], and morphine tolerance [187][150]. Lapatinib has been tested for the potential treatment of epileptic seizures [188][151], organophosphate-induced axonal damage in spinal cord [189][152], and Alzheimer’s disease [190,191][153][154]. Lorlatinib has been tested for the potential treatment of persistent pain [72][35]. Midostaurin has been tested for the potential treatment of traumatic spinal cord injury [192][155]. Neratinib has been tested for the potential treatment of AD [193][156].
Nilotinib has been tested for the potential treatment of epileptic seizures [194][157], tauopathies [40[3][4][158],41,195], alpha-synucleinopathies [40[3][5][159][160][161],42,196,197,198], TDP-43 pathology [64,65][27][28], beta-amyloid pathology [195][158], AD [60,199,200[23][162][163][164],201], Parkinson’s disease [202[165][166][167],203,204], chorea-acanthocytosis [205[168][169],206], and Niemann–Pick type A disease [184][147]. Palbociclib has been tested for the potential treatment of spinal muscular atrophy [207][170], amyloid beta-peptide pathology [208][171], and Parkinson’s disease [209][172]. Pazopanib has been tested for the potential treatment of tauopathy [210][173] and neurodegeneration-induced memory and cognitive deficits [211][174]. Pexidartinib has been tested for the potential treatment of intracerebral hemorrhage [212[175][176],213], subarachnoid hemorrhage [214][177], obesity-related cerebrovascular dysfunction [215][178], cognitive decline due to brain damage [216][179], tauopathy [217][180], AD [218[181][182],219], Huntington’s disease [220][183], multiple sclerosis [221[184][185][186],222,223], spinocerebellar ataxia type 1 [224][187], Down syndrome [225][188], peripheral nerve injury-induced mechanical hypersensitivity [226][189], cocaine addiction [227][190], and Parkinson’s disease [228][191]. Ponatinib has been tested for the potential treatment of ischemic stroke [229][192], epilepsy [230][193], and cerebral cavernous malformation [231][194].
Sorafenib has been tested for the potential treatment for subarachnoid hemorrhage [450][195], ischemic stroke [451][196], spinal cord injury [452][197], AD [69,453[32][198][199],454], Parkinson’s disease [455][200], multiple sclerosis [456[201][202],457], rabies [458][203], Rift Valley fever virus [459][204], alphaviruses [460][205], and Picornavirus enterovirus 71 [461][206]. Sunitinib has been tested for the potential treatment for traumatic brain injury [462][207], seizure [463][208], AD [464[209][210][211],465,466], Rett syndrome [68][31], cognitive impairment associated with HIV [467[212][213],468], dengue virus [469][214], and rabies [470][215]. Temsirolimus has been tested for the potential treatment for spinal cord injury [300][216], Parkinson’s disease [471[217][218],472], tauopathy [473[219][220],474], AD [475][221], spinocerebellar ataxia type 3 [476][222], nicotine withdrawal-associated cognitive deficits [477][223], and X-linked adrenoleukodystrophy [478][224]. Tofacitinib has been tested for the potential treatment for ischemic stroke [479][225], AD [480][226], multiple sclerosis [481,482][227][228], Parkinson’s disease [483][229], amyotrophic lateral sclerosis [484][230], and Venezuelan equine encephalitis virus [485][231]. Trametinib has been tested for the potential treatment for traumatic brain injury [486][232], aneurysmal subarachnoid hemorrhage [487][233], and brain arteriovenous malformations [488][234]. Vandetanib has been tested for the potential treatment for germinal matrix hemorrhage [489][235]. Lastly, Infigratinib has also been tested as a potential treatment for diabetic retinopathy [490][236].

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