Small Molecule Inhibitors for Hepatocellular Carcinoma: Advances and Challenges

HIGHLIGHTS: Multi tyrosine kinase inhibitors licensed for HCC treatment. Multi kinase inhibitors not licensed for HCC treatment. Inhibitors of Growth Factor Receptors. Small molecules acting as immunomodulators. Small molecules inhibiting crucial HCC pathways. Small molecules targeting various molecular targets. SIMPLE SUMMARY: Liver cancer is one of the most common types of cancer globally. Its treatment options have been limited. Sorafenib was the most commonly used drug with patients that have advanced liver cancer. Recently, multiple new target proteins and pathways, which play a major role in the disease, have been discovered. Accordingly, researchers have designed and revealed new drugs. Some of them are FDA approved and others are under investigation in clinical trials. The aim of our systematic review is to provide an overview of these recently reported targets and compounds. This review will be useful in identifying unpopular or underrated targets, as well as designing new combination treatment strategies. 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.