Liver Diseases: From Bench to Bedside

The human genome encodes at least 500 protein kinases, and among them, there are at least 90 tyrosine kinases [...].

Drug repurposing is increasingly becoming an attractive modality because it avoids risky compounds without the higher overall development costs and longer development of the drugs [5].Drug repurposing of preexisting drugs for the treatment of hepatitis A virus (HAV) infection has been reported [6].In this Special Issue, Sasaki-Tanaka et al. [7] examined the in vitro anti-HAV activity of 1134 US Food and Drug Administration (FDA)-approved drugs and finally found that masitinib, one of the TKIs, suppresses HAV replication, although further studies in vivo will be needed for clinical use.
Masitinib has a good safety profile at 7.5 mg/kg daily.Masitinib can increase overall survival and slow Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale-Revised (ALSFRS-R) deterioration among patients with ALS, which is a neurodegenerative disease with high mortality and morbidity rates affecting both upper and lower motor neurons [8].Masitinib has also been used in the treatment of various cancers or systemic mastocytosis because it is a novel TKI for numerous targets, including c-Kit (CD117), PDGFR, and FGFR [9][10][11].
Of interest, geldanamycin or herbimycin A could block HBV replication [14].Sorafenib, one of the TKIs used for advanced hepatocellular carcinoma, inhibits HBV and HCV replication [15][16][17][18].Schlevogt et al. [19] observed the occurrence of chronic HEV infection after treatment with the Bruton's tyrosine kinase inhibitor ibrutinib in vivo.Thus, some TKIs showed efficacy for the inhibition of hepatitis viral replication and cellular cytotoxicity to some extent (Table 1).
Although contrary opinions exist [20][21][22][23], careful attention should be paid to the reactivation and chronicity of hepatitis virus infection during the treatment of TKIs.Some TKIs should be useful for the control of hepatitis viral replication.TKIs also play a role in non-malignant diseases [24].
Imamura et al. [25] reported that the Src/c-Abl signaling pathway may be a potentially useful target for developing new drugs to treat ALS.They developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival, using motor neurons that were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation on superoxide dismutase 1 (SOD1).They found that bosutinib, which is one of the tyrosine kinase inhibitors to treat chronic myeloid leukemia (CML) [26], modestly extended the survival of a mouse model of ALS with an SOD1 mutation.A Phase I dose escalation study of bosutinib was performed for ALS patients [27].In this way, drug repurposing of TKIs to treat other diseases than malignant diseases is promising.
Diagnosis and treatment for liver diseases, including extrahepatic manifestations, have been progressing recently [28,29].Although nucleos(t)ide analogues and direct-acting antivirals are currently available and effective for HBV and HCV-related liver diseases, more effective and more convenient drugs may be needed for hepatitis virus infection.Drug repurposing of TKIs to treat hepatitis virus infection seems like one of the most hopeful and promising methods.

Table 1 .
Various tyrosine kinase inhibitors (TKIs) could inhibit the replication of hepatitis viruses.