Altering the bilayer motif in ERBB2 HER2 TMD and in ErbB HER TMD dimer causing in vitro and in vivo tumor suppression

The human ERBB2 is a transmembrane signaling tyrosine kinase receptor, which seems an ideal target of human WNT16B: the secreted growth factor possibly causing transmembrane domain (TMD) mutations. There is a strong relationship between the chemical nature of the TMD mutations and the potency with which they activate HER2. In silico, we have modelled the possible docking conformation of human WNT16B and human ERBB2 TMD homodimer, resulted a mutant complex. The ribbon structure, the C terminal and N terminal and GG4 like motif structures are similar in HER2 TMD and HER TMD: we modelled the WNT16B possible docking conformation to the HER1 TMD (ErbB), also resulted a mutant complex. If there is a strong relationship between TMD mutations improving the active dimer interface or stabilizing an activated conformation and the potency with which they activate HER2 (and possibly also HER), than the TMD dimerization part seems ideal reagent- target. The agent we have tested the 4 (Furan 2 yl)hepta 1,6-dien 4 ol (AKOS004122375) has very good connectivity attributes by its several rotatable bonds, and according to the in silico inspection of close residues intermolecular bonds, and the ligand docking, it can straight connect into the human ERBB2 TMD (HER2), and to the ErbB TMD (HER1) dimer bilayer motif as well. In silico, we also tested the agent ligands docking into the residues of human WNT16B and human ERBB2 TMD (HER2) mutant complex, and human WNT16B and human ErbB TMD (HER1) mutant complex. We tested the agent ligand in vitro, and in vivo several tumor models, highlighted that targeting the EGFRs TMD with an agent not only reducing the treatment- induced metastasis, but radically decreasing the tumor growth as well. Because of the analogous structure of HER2 TMD and HER TMD, this dimerization motif- targeting can be successful also in HER and HER2 EGFR signaling. In vitro we have reached 80% to 94% proliferation percentage in different tumor models, in vivo we have reached 35% to 61% tumor suppression in different tumor models, the metastasis inhibition effect of the compound was 82% to 87% in different tumor models.