T2

The chemokine SDF-1/CXCL12 and its receptors as targets of new antagonists for the treatment of inflammation, immune deficiency and cancer

Coordinators: D. Bonnaffe (Partner 14) and K. Balabanian (Partner 3)
Starting date: January 2012

The chemokine SDF-1/CXCL12 has been identified for its ability to stimulate B lymphocyte progenitors and hematopoietic stem cells but was shown later to play a large number of roles in many physiological processes such as development, inflammation and cancer. Being a chemokine, CXCL12 promotes cell migration but it displays additional functions such as cell growth promotion and prevention of apoptosis. During over 10 years, it was thought that CXCR4 was the only receptor mediating CXCL12 effects. However, Partner 3 showed that RDC1/CXCR7 is a second receptor for CXCL12.
A few antagonists of the CXCL12 axis have been developed. Most of them neutralize the interaction of CXCL12 with CXCR4 by binding to the receptor. So far, the non-peptidic compound AMD3100 bicyclam, a CXCR4 antagonist, is the only one approved for clinical use, in acute administration for the collection of hematopoietic stem cells (Mozobil, Plerixafor, Genzyme). However, AMD3100 is associated with cardiac toxicity and has a very short half-life (1 hr), preventing its chronic use. Targeting directly CXCL12 may also be performed using monoclonal antibodies or the neutraligand chalcone that inhibits the interaction of CXCL12 on both of its receptors.

This interdisciplinary project will involve chemists, biologists and physicians. Partner 3 provided key findings on the biological and pathological role of CXCL12 and its receptors, and offers rationales as well as cellular and pre-clinical models for the evaluation of antagonists of CXCL12 axis. Partner 8 addresses the mechanisms of resistance of tumors to irradiation. Partner 14 is expert in glycosaminoglycan (GAG) fragment synthesis as well as in unraveling new therapeutic targets and drug hits based on GAG-protein interaction regulation. Partner 15 has an acknowledged in high throughput screening using either commercial or patrimonial chemical libraries (more than 50000 drug-like, natural products and small chemicals). Partner 15 is also expert in in silico analyses of protein structure, allowing additional virtual screening within HTS platform. Once identified by screening, hit optimization can be provided by chemists involved in this project (Partners 14, 15).  Partner 13 has an extensive experience in deciphering the structural determinants of molecular interactions by NMR. Partner 16 is expert in the synthesis of lipid-based particles. The LERMIT platform network will provide all the necessary equipments and know-how, particularly for HTS and stem cell platform.

Based on its expertise, this consortium will develop two innovative strategies in clear rupture with respect to current paradigms on CXCL12 therapeutic modulation: 1) Development of CXCL12-binding Heparan Sulfate (HS) to block interactions of the chemokine with extracellular matrix (ECM) and cell surface GAGs (Aim 1); 2) Generation of molecules interfering with the intracellular trafficking and the expression of CXCR4 (Aim 2). Selected modulators of CXCL12 function will then be evaluated in cellular and animal models of inflammation, immune deficiency and cancer (Aim 3).