Abstract The antiproliferative transcriptional activity of the p53 tumor suppressor is inhibited by the binding of its transactivation domain to the regulator protein Mdm2. Overexpression of Mdm2 or amplification of its gene, leading to a loss of p53 function, has been observed in various tumors. An attractive approach to restore p53 activity in such tumors and to inhibit their growth is to prevent the association of the two proteins by blocking the p53 binding pocket of Mdm2 with a small molecule. In this presentation, we report how the starting point of CGM097 was discovered and how innovative medicinal chemistry efforts led to further optimization of the potency and physico-chemical properties, resulting in CGM097, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction. Citation Format: Keiichi Masuya, Pascal Furet, Stefan Stutz, Philipp Holzer, Carole Pissot-Soldmann, Nicole Buschmann, Thérèse Valat, Stéphane Ferretti, Stephan Ruetz, Caroline Rynn, Joerg Berghausen, Edgar Jacoby, Marc Lang, Tobias Gabriel, Francesco Hofmann, Joerg Kallen, Sébastien Jeay, Francois Gessier. Discovery of CGM097 as a novel Mdm2 inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr DDT01-01. doi:10.1158/1538-7445.AM2014-DDT01-01