Discovery of novel natural TEAD inhibitors for the chemoprevention of liver tumors

PROJECT SUMMARY/ABSTRACT
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a difficult disease to
treat and a leading cause of cancer deaths worldwide with increased incident rate in the US. HCC has well
characterized risk factors: chronic Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection, liver
cirrhosis and non-alcoholic steatohepatitis (NASH), which account for over 85% of all HCC cases. Such
well-defined population makes HCC an ideal type of malignancy for chemoprevention. However, currently
there is no prevention-interception drugs available for HCC. Hence, there is an imminent need to develop
effective agents to prevent and intercept liver cancer. Hippo pathway and its transcriptional regulators TEA
domain transcription factors (TEAD) and YAP/TAZ complexes have been shown to play important roles in
tumorigenesis. Studies from our and other labs have demonstrated the key roles of Hippo pathway in HCC
pathogenesis. Therefore, targeting TEAD-YAP/TAZ complex could be an effective strategy for HCC
prevention. Our long-term goal is to identify novel HCC-preventive natural products (NPs) from under-
explored Hawaiian microorganisms and other natural sources. The objective of this proposed research is
to discover NPs that inhibit TEAD palmitoylation for the prevention and interception of HCC. The central
hypothesis is that the under-explored Hawaiian microorganisms and NCI-NPs are excellent sources for
new cancer preventive NP discovery including TEAD-p inhibitors. The rationale of the proposed research
is that once novel potent TEAD palmitoylation inhibitors are identified, lead compounds will be studied for
their mechanisms of action and tested in vivo in the follow-up studies. The objectives of this project will be
accomplished by two specific aims: (1) Identify HCC relevant TEAD isoform(s), implement bioassay
development, and perform a pilot NP screening; (ii) Perform HTS, BGS, and structure determination of
active compounds In vitro and in vivo. The proposed project is significant and highly translational because
this multi-PI grant aims at identifying novel NPs which inhibit TEAD palmitoylation for HCC prevention and
interception. The results will likely lead to new chemoprevention trials to investigate these new NPs in
high-risk HCC population. This would have a profound effect to reduce the burden of HCC all over the
world.

Grant Number: 5UG3CA290375-03
NIH Institute/Center: NIH
Principal Investigator: Shugeng Cao