The TCTP protein, overexpressed in many tumor cells, has a pro-survival role through its anti-apoptotic properties and through the control of cellular levels of p53. TCTP therefore represents a target of interest for antitumours. The team of A. Telerman/R. Amson of the Gustave Roussy Institute having shown that the antidepressant sertraline (Zoloft) restores high levels of p53, two clinical trials were conducted with sertraline alone or in combination on patients with acute myeloid leukemia. Preliminary experiments of SPR having suggested a direct action of sertraline on TCTP and to improve TCTP inhibitors, a complete study of interaction of TCTP by NMR, TSA, ITC, SPR, BLI techniques was undertaken at theInstitute of Chemistry of Natural Substances - ICSN (CNRS/UPSaclay, Gif-sur-Yvette), at BioCIS (Orsay), at the DCM in Grenoble and at the CRCM in Marseille. The revised affinity is much lower (with a Kd of the order of ~mM) than initially proposed (~50 µM) and the scientists proposed in an article published in ChemMedChem another possible and indirect mode of action of sertraline on TCTP and p53 not requiring its entry into the cell.

The anti-apoptotic properties of TCTP come through stimulation of the anti-apoptotic properties of Bcl-xL and Mcl-1 proteins at the mitochondria. TCTP contains a BH3 domain buried in the globular structure and responsible for the interaction with Bcl-xL. In a second study published in Journal Biological Chemistry, the authors showed by NMR, biochemistry (INSC) and SAXS (Synchrotron Sun) that this BH3 domain of TCTP also interacts with Mcl-1 to form a very dynamic complex at the interface and associated with a very strong weakening of the globular domain of TCTP.

A better understanding of the structural plasticity of TCTP is essential not only to understand its anti-apoptotic action but also for the future research of antitumor drugs targeting TCTP. Very high field NMR, and in particular the 950 MHz Infranalytics spectrometer at Gif-sur-Yvette, have provided crucial information here in this context.

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