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.

Virtual Screening and Biological Evaluation of Potential PD-1/PD-L1 Immune Checkpoint Inhibitors as Anti-Hepatocellular Carcinoma Agents

“…Disrupting the PD-L1-mediated tumor immune escape by SMIs is more advantageous over monoclonal anti-bodies (mAbs). Despite their positive therapeutic efficacy, mAbs suffer from many limitations such as immune-related side effects (irAEs), complex production process, high treatment costs, and low permeability in the tumor tissues. − On the other hand, SMIs have better oral bioavailability and tumor penetration, easier self-administration and have fewer side effects compared to mAbs, making immunomodulation by SMI an attractive approach for cancer treatment as reviewed . The increasing number of available crystal structures for PD-L1 bound to inhibitors helped in understanding the mechanism of inhibition of these compounds and paved the way for discovery of novel PD-L1 inhibitors. , …”

“…30−32 On the other hand, SMIs have better oral bioavailability and tumor penetration, easier self-administration and have fewer side effects compared to mAbs, 30 making immunomodulation by SMI an attractive approach for cancer treatment as reviewed. 33 The increasing number of available crystal structures for PD-L1 bound to inhibitors helped in understanding the mechanism of inhibition of these compounds and paved the way for discovery of novel PD-L1 inhibitors. 11,13 In this study, the 3D crystal structure of human PD-L1 protein complexed with a SMI was used to design a sequential VS protocol comprising pharmacophore screening followed by molecular docking.…”

Antitumor immunostimulatory activity of the traditional Chinese medicine polysaccharide on hepatocellular carcinoma

“…According to the data provided by the World Health Organization (WHO), hepatocellular carcinoma (HCC) is the world’s sixth most common malignant tumor and the third leading cause of cancer death worldwide in 2020 ( 1 ). It is characterized by a short duration of illness and is difficult to heal, and the invasion, metastasis, and spread of HCC cells are the reasons for the high mortality rate of this disease ( 2 ).…”

Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries

“…Sorafenib (NEXAVAR; SOR) is a multi-target protein kinase inhibitor approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma [ 39 , 40 ]. Although SOR has not been approved for lung cancer, it is still the subject of extensive research related to lung cancer [ 41 , 42 , 43 ].…”