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

Abstract

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.

Keywords: aberrant cell cycle disease; cancers; kinase inhibitors; neurological disorders.

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.