FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders

Cancers and neurological disorders are two major types of diseases. We previously developed a new concept termed “Aberrant Cell Cycle Diseases” (ACCD), revealing that these two diseases share a common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested as kinase/oncogene activation and tumor suppressor inactivation, which are hallmarks of both tumor growth in cancers and neuronal death in neurological disorders. Therefore, some cancer therapies (e.g., kinase inhibition, tumor suppressor elevation) can be leveraged for neurological treatments. 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. In this review, we list these 74 FDA-approved kinase-targeted drugs and identify those that have been reported in preclinical and/or clinical trials for neurological disorders, with a purpose of discussing the feasibility and applicability of leveraging these cancer drugs (FDA-approved kinase inhibitors) for neurological treatments.

Since kinases are implicated in the process of the cell cycle, kinase inhibitors should be able to block the cell cycle for the treatment of both cancers and neurological disorders. Indeed, compelling evidence shows that a single agent inhibiting the same kinase(s) can treat both cancers and neurological disorders. There is a long list of such agents: CDK inhibitor (roscovitine), SFK inhibitor (PP2), ERK inhibitor (PD98059), ROCK inhibitor (Y-27632), STAT inhibitor (WP1066), mTOR inhibitor (RAD001), and Wnt inhibitor (CWP232291), amongst others. For example, several labs reported that the Src inhibitor PP2 kills cancer Figure 1. The schematic of "aberrant cell cycle diseases". The molecules and related mitogenic pathways contributing to the aberrant cell cycle re-entry that is associated with not only tumorigenesis in cancers, but also neuronal death in neurological diseases. The arrows do not necessarily indicate direct binding and/or activation of the downstream molecules; intermediate proteins or kinases may exist. Akt: protein kinase B; Ca2+: calcium; Cdk: cyclin-dependent kinase; COX2: cyclooxygenase-2; Csk: c-terminal Src kinase; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal-regulated kinase; FAK: focal adhesion kinase; GPCR: G protein-coupled receptor; GSK3β: glycogen synthase-3 beta; IP3: inositol trisphosphate; JAK: Janus kinase; JNK: c-Jun N-terminal kinases; MEK: mitogen-activated protein kinase kinase; MLK: mixed lineage kinases; mTOR: mammalian target of rapamycin; NF-kB: nuclear factor kappa B; NO: nitric oxide; PGE2: prostaglandin E2; PI3K: phosphatidylinositol 3-kinase; PLC: phospholipase C; Ras: rat sarcoma virus kinase; Rac1: ras-related C3 botulinum toxin substrate 1; Raf: rapidly accelerated fibrosarcoma; ROS: reactive oxygen species; SFKs: Src family kinases; STAT: signal transducer and activator of transcription Figure 1. The schematic of "aberrant cell cycle diseases". The molecules and related mitogenic pathways contributing to the aberrant cell cycle re-entry that is associated with not only tumorigenesis in cancers, but also neuronal death in neurological diseases. The arrows do not necessarily indicate direct binding and/or activation of the downstream molecules; intermediate proteins or kinases may exist. Akt: protein kinase B; Ca 2+ : calcium; Cdk: cyclin-dependent kinase; COX2: cyclooxygenase-2; Csk: c-terminal Src kinase; eNOS: endothelial nitric oxide synthase; ERK: extracellular signalregulated kinase; FAK: focal adhesion kinase; GPCR: G protein-coupled receptor; GSK3β: glycogen synthase-3 beta; IP3: inositol trisphosphate; JAK: Janus kinase; JNK: c-Jun N-terminal kinases; MEK: mitogen-activated protein kinase kinase; MLK: mixed lineage kinases; mTOR: mammalian target of rapamycin; NF-kB: nuclear factor kappa B; NO: nitric oxide; PGE2: prostaglandin E2; PI3K: phosphatidylinositol 3-kinase; PLC: phospholipase C; Ras: rat sarcoma virus kinase; Rac1: ras-related C3 botulinum toxin substrate 1; Raf: rapidly accelerated fibrosarcoma; ROS: reactive oxygen species; SFKs: Src family kinases; STAT: signal transducer and activator of transcription.
Following the golden era of cancer drug development in the past few decades, the United States Food and Drug Administration (US FDA) has approved numerous cancer therapies (e.g., RNAi gene therapy, nanoparticle-based in vivo drug delivery reagents, kinase-targeted drugs, and CAR T-cell therapy, as well as others). In contrast, there are very few FDA-approved drugs that benefit patients with certain neurological disorders, such as Alzheimer's disease (AD), intracerebral hemorrhage (ICH), ischemic stroke (IS), traumatic brain injury (TBI), and other disorders. If state-of-the-art approaches of cancer therapies can be applied to neurological treatments, new breakthroughs will very likely arise in the development of neurological drugs. 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]. Bosutinib was also found to promote autophagy and clear protein aggregates in neurons [41,42]. 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 antiepileptic 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]. 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.
Sunitinib is a tyrosine kinase inhibitor, which has been studied in clinical trials to treat both neovascular age-related macular degeneration and diabetic macular edema secondary to retinal vein occlusion. The clinical use of sunitinib for neovascular age-related macular degeneration (NCT03249740) completed phase I clinical trials in 2019. This study tested increasing doses of sunitinib injected intravitreally compared to aflibercept. No data has been published at this time. The use of sunitinib for diabetic macular edema secondary to retinal vein occlusion (NCT04085341) completed phase II trials in 2021. This study specifically looked at the dosing of this compound in patients who had prior treatment with anti-vascular endothelial growth factor.
Temsirolimus, a prodrug of sirolimus and an mTOR inhibitor, has been used in clinical trials for relapsing-remitting multiple sclerosis (NCT00228397). Phase II clinical trials were conducted to assess the long-term tolerability and safety of three different doses of temsirolimus. Tofacitinib, a janus kinase enzyme inhibitor, has been used in three different clinical trials involving neurological disorders: myasthenia gravis, Down syndrome, and depression. Recruiting is underway for an early phase I trial to use tofacitinib in patients with myasthenia gravis (NCT04431895) with the goal to significantly improve quantita-tive myasthenia gravis scores from a baseline measurement after six months. Currently, a phase II trial using tofacitinib in patients with Down syndrome to treat a multitude of different skin conditions (alopecia areata, atopic dermatitis/eczema, psoriasis, etc.) (NCT04246372) is underway. Lastly, a phase I/II clinical trial comparing tofacitinib to placebo to treat treatment-resistant depression (NCT04141904) had been suspended due to the COVID-19 pandemic.
Trametinib, an MEK inhibitor, is being used in a phase I/II clinical trial for amyotrophic lateral sclerosis (NCT04326283). In this study, researchers will focus on the safety, tolerability, and efficacy of trametinib in ALS patients. Upadacitinib, a selective JAK1 inhibitor, is currently going through phase III trials to treat giant cell arthritis (NCT03725202). In this study, the efficacy of upadacitinib plus corticosteroids is being assessed compared to corticosteroids alone. Finally, a recent phase II trial (NCT05356858) is studying the efficacy and safety of zanubrutinib, a BTK inhibitor, in patients with recurrent neuromyelitis optica spectrum disease, a disease where the immune system damages the optic nerves and spinal cord.

Conclusions and Discussions
In summary, there are 16 FDA-approved kinase inhibitors that have been tested in clinical trials for neurological treatments. Since almost all 74 FDA-approved kinase inhibitors have been examined in various animal models of neurological disorders, it appears that more FDA-approved kinase inhibitors will enter clinical trials for neurological treatments in the future. In accordance with the Generics and Biosimilars Initiative, the FDA-approved drugs (including kinase inhibitors) will become available commercially at relatively low prices after expiration of their existing patents. We are optimistic that this repurposing strategy is likely to provide safe, effective, and affordable therapies for neurological disorders.
It is important to note that kinases are also involved in the division of neural stem cells that are associated with neurogenesis and self-repair after brain injury. Therefore, optimization of the dosing regimen of a kinase inhibitor or the combination of a few kinase inhibitors is needed to increase efficacy while reducing side effects, when repurposing the kinase inhibitor(s) to treat neurological disorders.