Developing YAP/TEAD Inhibitors for Novel NASH-Associated Hepatocellular Carcinoma Therapeutics
Abstract
This project is to propose a potential novel therapeutic option for liver cancer. Hepatocytes maintain vital functions in our body, but they are prone to damages resulting from alcoholism, obesity, viral infection, and drug toxicity in chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is usually part of the metabolic syndrome found in patients who do not drink alcohol but develop fatty livers due to diabetes mellitus, hypertension, dyslipidemia, obesity, and insulin resistance. Nonalcoholic steatohepatitis (NASH) is advanced form of NAFLD with complications such as inflammation and liver scarring. This long- term hepatic damage ultimately activates oncogenic pathways that transform hepatocytes into tumor phenotypes known as hepatocellular carcinoma (HCC). Current immunotherapy shows promising effects on inhibiting HCC in patients who suffer hepatitis B or C. However, NASH limits anti-tumor surveillance in immunotherapy. Sorafenib is the first line option of drugs in anti-HCC targeted therapy and has been shown to improve patient’s survival rate in the short term. However, resistance to this drug eventually develops leading to failure of the treatment. Drug resistance remains the principal cause of treatment failure during the use of targeted therapies. Yes-associated protein (YAP) is an oncogenic protein and acts as a transcriptional coactivator for Tea domain transcription factors (TEAD). YAP activation through forming complexes with TEAD induces arrays of target genes for HCC survival and growth. The YAP/TEAD complex not only drives tumorigenesis but also confers to drug resistance. Activated YAP induces molecules that can allow HCC escape from death and gain resistance to drugs such as Sorafenib. Currently, there is no FDA-approved drug available to disrupt the YAP/TEAD complex. YAP interacts with TEAD with three interfaces. Considering that TEAD molecules appear to be largely dispensable for normal functions of our body, its inhibition by our compounds should not result in major adverse toxicity effects. Our intention is to discover the first-in-class small molecule drugs that disrupt interface 3 in TEAD because our initial studies have demonstrated that disrupting interface 3 greatly weakens YAP binding while preserving tumor suppressor protein VGLL4 binding at interfaces 1 and 2. In order to design potent, specific, easy-to-make and drug-like molecules, we use computational intelligence to re-engineer a new set of compounds that are potent and efficient for inhibition of YAP/TEAD interaction. In addition, we have developed very sensitive reporter systems that allow us to assess the inhibitory activities of candidate compounds in cultured tumor cells and in animals with implanted HCCs. HCC development is a stepwise chronic liver disease process that may take several decades to evolve in human. However, it is difficult to follow changes of liver histology in patients due to the asymptomatic nature of NASH to HCC transition during early stages. Patients with liver function failure are often at advanced stages of the diseases, and therefore the only option for treatment is to carry out a liver transplantation. However, liver donors are limited every year. There is an urgent need to identify molecular targets and develop anti-HCC therapy for the treatment of NASH. We have also established a preclinical model that faithfully induces human liver pathologies of NASH, fibrosis, and HCC in the setting of YAP overexpression. This model enables us to determine whether our candidate compounds can synergize with Sorafenib and inhibit NASH progress to HCC. Knowledge obtained in this proposal may open new avenues for therapeutic strategies by targeting the oncogenic YAP/TEAD pathway against liver pathologies such as NASH, fibrosis, cirrhosis, and HCC, benefitting the health and well-being of military members, Veterans, their beneficiaries, and the general public who are prone to NASH, alco
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310737
Entities
People
- Chenglong Li
Organizations
- United States Army
- University of Florida