Small Molecule Inhibitors for Hepatocellular Carcinoma: Advances and Challenges

Abstract

According to data provided by World Health Organization, hepatocellular carcinoma (HCC) is the sixth most common cause of deaths due to cancer worldwide. Tremendous progress has been achieved over the last 10 years developing novel agents for HCC treatment, including small-molecule kinase inhibitors. Several small molecule inhibitors currently form the core of HCC treatment due to their versatility since they would be more easily absorbed and have higher oral bioavailability, thus easier to formulate and administer to patients. In addition, they can be altered structurally to have greater volumes of distribution, allowing them to block extravascular molecular targets and to accumulate in a high concentration in the tumor microenvironment. Moreover, they can be designed to have shortened half-lives to control for immune-related adverse events. Most importantly, they would spare patients, healthcare institutions, and society as a whole from the burden of high drug costs. The present review provides an overview of the pharmaceutical compounds that are licensed for HCC treatment and other emerging compounds that are still investigated in preclinical and clinical trials. These molecules are targeting different molecular targets and pathways that are proven to be involved in the pathogenesis of the disease.

Keywords: HCC pathways inhibitors; growth factor receptors inhibitors; hepatocellular carcinoma; molecular targets; small molecule inhibitors; small molecules as immunomodulators; tyrosine kinase inhibitors.

Figure 1

Flow diagram of the literature screening process including number of records retrieved from search databases, exclusion and inclusion criteria.

Figure 2

Schematic representation of research interest toward small molecule inhibitors in liver cancer treatment. Y-axis represents number of studies and X-axis represent years. These data were collected from PubMed.

Figure 3

The chronological sequence of the currently FDA approved small molecule inhibitors in HCC and their primary molecular targets.

Figure 4

Schematic representation of combinational therapies of sorafenib and other small molecule inhibitors discussed in this review. This simplified schematic does not contain all signal transduction molecules known to be involved in the described signaling cascades but focuses on the targets discussed in this review. This figure was generated by biorender. STAT, Signal transducer and activator of transcription 3; JNK, c-Jun N-terminal kinase; NEDD-8, neural precursor cell expressed developmentally downregulated 8; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; HMG co-A, β-Hydroxy β-methylglutaryl-CoA; RAS, Rat sarcoma virus; MEK, Mitogen-activated protein kinase; ERKs, extracellular signal-regulated kinases; PI3K, Phosphatidylinositol 3-kinase; PDK1, 3-Phosphoinositide-dependent protein kinase 1; AKT, Ak strain transforming; mTOR, mammalian target of rapamycin; INF-lamda 3, Interferon lambda-3; ROS, Reactive oxygen species.

Figure 5

Schematic representations of FDA approved (indicated in red) and not licensed (indicated in black) small molecule inhibitors of tyrosine kinase receptors and other pathways in HCC discussed in this review. This figure was generated by biorender. EGFR, Epidermal Growth Factor Receptor; FGFR, Fibroblast Growth Factor Receptor; VEGFR, Vascular Endothelial Growth Factor Receptor; PDGFR, Platelet Derived Growth Factor Receptor; HGFR, Hepatocyte Growth Factor Receptor; IGF, Insulin Growth Factor Receptor.

Figure 6

Schematic representations of emerging small molecule inhibitors of Wnt signaling pathway and STAT3 signaling pathway. This figure was generated by biorender. Wnt, Wingless and Int-1; TCF/LEF, T-cell factor/lymphoid enhancer-binding factor; GSK-3β, glycogen synthase kinase-3 beta; APC, Adenomatous Polyposis Coli; LRP, lipoprotein receptor-related protein; JAK, Janus Kinase.