THE SCIENCE BEHIND
ANG-3777 is a small molecule designed to mimic the biological activity of HGF, thereby activating the c-Met cascade of pathways involved in tissue repair and organ recovery. ANG-3777 has demonstrated several similarities to HGF, including c-Met dependence and selective c-Met receptor activation, without acting on other growth factor receptors. In addition, it has a substantially longer half-life than HGF.*
*ANG-3777 is an investigational product and is not approved by any regulatory authority.
THE ROLE OF THE HEPATOCYTE GROWTH FACTOR/C-MET PATHWAY IN ACUTE ORGAN INJURY
Decades of research have led to a deep understanding of the hepatocyte growth factor (HGF)/c-MET pathway and the role it plays in the repair of injured organs.
When an organ is injured, the body releases HGF into the blood. HGF then travels to the site of the injury and binds to the promoter region of the c-Met receptor gene on cells in that location. HGF is the only ligand known to bind to c-Met and cause its activation. The binding of HGF to c-Met triggers a series of downstream proteins responsible for preventing apoptosis (cell death), stimulating cell proliferation, promoting angiogenesis (formation of new blood vessels), improving cellular motility, and remodeling the extracellular matrix, all in order to restore normal structure and function to the injured organ.
In the illustrative diagram to the left, some of the essential proteins in transducing and amplifying the c-Met signal are shown, along with a representative set of actions these proteins are responsible for inducing. For instance, the adaptor proteins Grb2, SHC, and Gab1, among others, are responsible for recruiting downstream signaling proteins including the following (and some of their respective actions):
- Ras-Raf-MEK-ERK/MAPK: Increase in mRNA translation, promote angiogenesis, stimulate cell proliferation, prevent apoptosis and promote tubulogenesis (restoring normal tissue architecture)
- PI3K: Increase cell motility, promote tubulogenesis, prevent apoptosis and induce cellular differentiation
- AKT/mTOR: Prevent apoptosis, increase metabolism, increase cell motility, promote angiogenesis and transcription regulation
- Stat-3: Stimulate cell proliferation, prevent apoptosis and induce cellular differentiation
- FAK: alter cellular adhesion, increase cell motility and promote angiogenesis.
HGF/c-Met also downregulates the pro-fibrotic cytokine TGF-β (transforming growth factor beta) to prevent the organ from entering the progressive cycle of fibrosis (growth inhibition, extracellular matrix deposition and cell death). These interactions are influenced by the cellular environment in which these pathways are activated. For example, in the setting of ischemia-reperfusion injury, c-Met is upregulated and HGF/c-Met signaling is amplified, thereby initiating the cascade of organ repair.
As shown in the following figure, HGF is released into circulation and reaches peak concentration levels approximately two hours after acute organ injury (the solid blue line). However, the c-Met receptor is synthesized more slowly (dashed orange line) and peaks approximately 24 hours following the injury, resulting in insufficient levels of HGF available relative to the peak expression levels of c-Met on the cell surface. 1
Our founder and current Executive Chairman and Chief Scientific Officer, Itzhak Goldberg, M.D., has made seminal contributions to the understanding of HGF and fibrotic pathways. The HGF/c-Met pathway has been the target of significant scientific interest, with over 14,000 papers and abstracts since its initial identification in the 1980s.2 This pathway has been studied in many different disease models, including in over 300 papers/abstracts on kidney injury between 1990 and 2020 and over 200 papers/abstracts on lung injury between 1989 and 2020.3,4
- Liu Y, et al. Up-regulation of hepatocyte growth receptor: an amplification and targeting mechanism for hepatocyte growth factor action in acute renal failure.” Kidney International (1999); 55: 442–453.
- https://pubmed.ncbi.nlm.nih.gov/?term=Hepatocyte+growth+factor&filter=years.1981-2020&timeline=expanded. Accessed January 31, 2020.
- https://pubmed.ncbi.nlm.nih.gov/?term=Hepatocyte%20growth%20factor%2C%20kidney%20injury&timeline=expanded. Accessed January 31, 2020.
- https://pubmed.ncbi.nlm.nih.gov/?term=Hepatocyte+growth+factor%2C+lung+injury&timeline=expanded. Accessed May 27, 2020.