DS0401 - Etude des systèmes biologiques, de leur dynamique, des interactions et inter-conversions au niveau moléculaire

A new approach to inhibit ErbB2 signaling and design new drug candidates: targeting the EGF domains of its membrane partner, the MUC4 mucin – DRUG_MUC4

MUC4 therapeutic targeting in cancer

The general goal of the DRUG_MUC4 project is to study the structure-function relationship of the MUC4-ErbB2 complex and propose new small inhibiting therapeutic molecules targeting MUC4-EGF domains.<br />The aberrant overexpression of the transmembrane MUC4 mucin, its partnership with ErbB2 and the negative consequences of the activity of MUC4-ErbB2 complex on epithelial homeostasis, has allowed identification of MUC4 as a highly attractive therapeutic target (Kufe, 2009).

Identify real hits and define 3D structure

The general goal of the DRUG_MUC4 project is to study the structure-function relationship of the MUC4-ErbB2 complex and propose new small inhibiting therapeutic molecules targeting MUC4-EGF domains.<br />The main aim of that project is to understand for the first time how the EGF domains of MUC4 interact with ErbB2 receptor and based on the structural observations design new small inhibitory molecules that could become therapeutic tools in epithelial disorders to disrupt MUC4-ErbB2 complex.

In the DRUG_MUC4 project, computational virtual screening (Villoutreix et al., 2007; Renault et al., 2013) is the chosen strategy to identify and design PPI inhibitors (i-PPI) that will directly compete with the MUC4-EGF domains of the MUC4-ErbB2 interface complex. Large compound libraries in the range of millions of compounds have been rationally screened by docking a pharmacophore approach, focusing a small subset of virtual hits which will be assessed by biological assays (in vitro and in vivo) to identify real hits. MicroScale Thermophoresis (MST), Surface Plasmon Resonance (SPR) and Förster Resonance Energy Transfer (FRET) technologies will be used to evaluate the inhibitory capacities of the selected compounds. In parallel, the 3D structure of the EGF domains and of the MUC4-ErbB2 complex will be established to precisely describe the interaction and optimize compounds. Compounds displaying the most potent inhibitory capacities and biological activities (in vitro and in vivo) will be selected as the starting point of a medicinal chemistry program to design the best MUC4-ErbB2 lead inhibitors.

Biological activities of EGF1 and EGF2 have been determined. Modelling of MUC4-ErbB2 has been performed and inhibitory molécules have been identified.

We will continue our work to better characterize the inhibitory molecules and molecular interaction

We do not communicate at this time (patents)

The general goal of the DRUG_MUC4 project is to study the structure-function relationship of the MUC4-ErbB2 complex and propose new small inhibiting therapeutic molecules targeting MUC4-EGF1/2 domains.
The aberrant overexpression of the transmembrane MUC4 mucin in diverse pathologies of the epithelium, its partnership with ErbB2 and the negative consequences of the activity of MUC4-ErbB2 complex on epithelial homeostasis, has allowed identification of MUC4 as a highly attractive therapeutic target (Kufe, 2009).
The MUC4 membrane-bound mucin belongs to a family of large O-glycoproteins involved in cell-cell interactions that serves as an extracellular sensor of the immediate cell environment (Jonckheere and Van Seuningen, 2008 ; 2010). At the cell surface MUC4 is the only known partner of oncogenic receptor ErbB2 where they form an active complex involved in cell proliferation, cell differentiation and apoptosis. From these data MUC4 has been proposed as a modulator of cell proliferation and cell differentiation (Jonckheere et al., 2008). Moreover, expression studies have shown that MUC4 and ErbB2 are overexpressed in numerous pathologies of the epithelium with detrimental consequences on the homeostasis of epithelial cells and mucosa (Jonckheere and Van Seuningen, 2010, Jonckheeere et al., 2014).
Recently, MUC4-ErbB2 complex has started to be understood at the molecular level and biochemical studies conducted in our laboratory have shown that the physical interaction between human MUC4 and ErbB2 involves a region of the extracellular domain of MUC4 composed of three EGF-like domains (Jonckheere et al., 2012). We have also shown using molecular prediction that these EGF domains are conserved throughout evolution and structurally equivalent to hEGF (Jonckheere et al., 2013) and that MUC4-EGF1 and MUC4-EGF2 domains are biologically active (unpublished).
The MUC4-ErbB2 complex having important detrimental effects in human epithelial pathophysiology, and therapies targeting ErbB2 being not always successful, we propose in this original, multidisciplinary and ambitious project a new approach by targeting MUC4-EGF1/2 domains via the inhibition of protein-protein interaction (PPI) between MUC4 and ErbB2. New ligands inhibiting the interaction will be conceived using a structure-based drug design (SBDD) approach. This may represent a new efficient alternative to treat epithelial diseases associated with MUC4-ErbB2 overexpression when ErbB2 targeting has failed. Economically, the discovery of new drugs targeting MUC4 would help reduce the cost of disease and increase patient survival and quality of life.
In the DRUG_MUC4 project, computational virtual screening (Villoutreix et al., 2007; Renault et al., 2013) is the chosen strategy to identify and design PPI inhibitors (i-PPI) that will directly compete with the MUC4-EGF1/2 domains of the MUC4-ErbB2 interface complex. Large compound libraries in the range of millions of compounds have been rationally screened by docking a pharmacophore approach, focusing a small subset of virtual hits which will be assessed by biological assays (in vitro and in vivo) to identify real hits. MicroScale Thermophoresis (MST), Surface Plasmon Resonance (SPR) and Förster Resonance Energy Transfer (FRET) technologies will be used to evaluate the inhibitory capacities of the selected compounds. In parallel, the 3D structure of the MUC4-EGF1/2 domains and of the MUC4-ErbB2 complex will be established to precisely describe the interaction and optimize compounds. Compounds displaying the most potent inhibitory capacities and biological activities (in vitro and in vivo) will be selected as the starting point of a medicinal chemistry program to design the best MUC4-ErbB2 inhibitors.

The DRUG_MUC4 project aims at:
1- Modelling the MUC4-EGF/ErbB2 interaction,
2- Solving the 3D structures of MUC4-EGF1, MUC4-EGF2 and of MUC4-ErbB2 complex,
3- Elaborating and testing drug-candidates disassembling the MUC4-ErbB2 complex.

Project coordination

Isabelle VANSEUNINGEN (Inserm UMR-S1172/JPARC/Equipe Mucines, différenciation et cancérogenèse épithéliales)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Université de Lille 2 Plate-forme "Interactions moléculaires"
Inserm Inserm UMR-S1172/JPARC/Equipe Mucines, différenciation et cancérogenèse épithéliales
Inserm Inserm UMR-S1172/JPARC/Equipe Facteurs de persistence des cellules leucémiques
Inserm Inserm UMR-S1172/JPARC/Equipe Onco- et NeuroChimie
CNRS Laboratoire de Biologie Structurale

Help of the ANR 494,685 euros
Beginning and duration of the scientific project: December 2015 - 36 Months

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