P-glycoprotein (Pgp) limit intracellular drug accumulation by ATP-dependent extrusion of therapeutic agents out of cells. In cancer cells, over-expression of drug efflux transporters is associated with multidrug resistance (MDR) process.

Design of peptidomimetics as efflux pump inhibitors

Project manager : L. Ettouati

We keep working on development of ABC-transporters ligands such as (aza)peptidomimetics derived of reversines (Scheme). We have several sets of dipeptides (Hyp and aza series) with different pharmacological profiles, e.g. as selective BCRP inhibitors or selective Pgp inhibitors or mixed ones.


This work relies on a network of partners to streamline and optimize our scientific approach (molecular modeling, pharmaceutical formulation, selectivity, in vivo evaluation).

Publications :

J. Paris, P. Falson, A. Di Pietro, O. Arnaud et M.E. Million. Nouveaux composés de type azapeptide ou azapeptidomimétique, inhibiteurs de BCRP et/ou P-gp. French Patent FR2941956A1 published Jan 26 2009. PCT WO 2010/084292 published Jul 29 2010.
O. Arnaud, A. Koubeissi, L. Ettouati, R. Terreux, G. Alamé, C. Grenot, C. Dumontet, A. Di Pietro, J. Paris et P. Falson. Potent and fully non-competitive inhibitor of multidrug resistance P-glycoprotein. J. Med. Chem., 2010, 53, 6720-6729.

A. Arnaud, A. Koubeissi, L. Ettouati, J. Paris, A. di Pietro et P. Falson. Modulateurs peptidiques et peptidomimétiques non compétitifs spécifiques de la glycoprotéine P. French Patent FR2950888A1, published Apr 8 2011. PCT WO 2011/042654 published Apr 11 2011.

• Dr. Pierre FALSON (IBCP - UMR 5086 - Laboratoire des Protéines de Résistance des Agents Chimiothérapeutiques)
• Pr. Charles DUMONTET (CRCL, UMR Inserm 1052 CNRS 5286)
• Dr. Attilio DI PIETRO (IBCP - UMR 5086 - Laboratoire des Protéines de Résistance des Agents Chimiothérapeutiques)

Synthesis and biological evaluation of new steroids as Pgp inhibitors

Steroids have been reported to influence MDR by inhibiting the cellular extrusion of cancer chemotherapeutics.

Previously, our research group found (1) new steroids derivatives as Pgp inhibitors, the general structure of this compounds is represented on figure 1. We have developed Pgp inhibitors series from deoxycholic acid and chenodeoxychiolic acid (scheme 1).

We have developed a new pathway for the synthesis of heterosteroids (scheme 2) from bile acids and we wish to apply this new strategy for the synthesis of Pgp inhibitors. 

(1) Grenot, C.; Cuilleron, C. Y. New steroid inhibitors of Pgp for use for inhibiting multidrug resistance. WO2011/73419 A1.
(2) Ibrahim-Ouali, M.; Botsi-Nkomendi, N.; Rocheblave, L., Synthesis of heterosteroids. First synthesis of oxa steroid from cholic acid. Tetrahedron Letters 2010, 51, (1), 93-95.
(3) Ibrahim-Ouali, M.; Hamze, K.; Rocheblave, L., Synthesis of 12-oxa, 12-aza and 12-thia cholanetriols. Steroids 2011, 76, (3), 324-330.

• Pr. Charles DUMONTET (CRCL, UMR Inserm 1052, CNRS 5286)
• Dr. Malika IBRAHIM-OUALI (iSm2, UMR 7213 Marseille)
• Pr. Raphaël TERREUX (IBCP, UMR 5086)