Derivats de la Neuregulina per bloquejar el receptor HER en cèl·lules tumorals que el sobreexpressen

Abstract

Cancer is a disease that affects a large part of the world’s population, no matter the location nor the gender of the person. The scientific and medical community has done much research to inhibit tumor growth and slow down the process of metastasis. Some of these new treatments are directed against overexpressed markers in cancer, like the HER receptor family. HER3 is a protein of the cell membrane which does not have tyrosin-kinase activity, so it cannot phosphorylate its intracellular domain. It needs another receptor of the family to dimerize and thus be able to make its function. This specific binding with another receptor is mediated by its ligand, neuregulin. Once HER3 dimerizes with EGFR, HER2, or HER4 it triggers a bunch of intracellular signaling pathways that cause overgrowth and proliferation of cancerous cells if these receptors are deregulated. Nowadays, several targeted therapies that recognize these biomarkers involved in tumor processes are being developed. For instance, some of these treatments are the creation of specific antibodies or intracellular domain-inhibitors. In this work, a strategy is proposed based on the modification of the ligand of HER3, like neuregulin-1, in order to acquire an increased affinity for its receptor. The studies indicate that amino acid changes located in the egf domain, the region of the ligand that interacts with HER3, could change the binding affinity, as well as amino acid changes located on the peripheral region could form new bonds with the receptor. With these, vehicular peptides (PDC) can be created, which consists in the modified-neuregulin bound to a therapeutic agent that could release cytotoxic compounds into HER3-overexpressing cells. This final degree project consists on a bibliographic research that includes the study of the interaction between the ligand and the receptor, the consequences once HER3 dimerizes, and the state of the art on targeted therapies. Furthermore, a ligand-modified based model is proposed, using informatic programs to study the molecular dynamics of the modified and the wild-type neuregulin-1, and a subsequent docking simulation to predict the studied and novel interactions