Abstract 3996: Pyridoclax and its derivatives from oligopyridine family directly inhibit Mcl-1 and exert potent antitumor effects on ovarian cancer in vitro and in vivo

Abstract

Abstract Ovarian cancer is the leading cause of death from gynecological malignancies worldwide. Although the patients are initially quite sensitive to the taxane and platinum-based first-line chemotherapy, most of them relapse and develop chemoresistance. Defects in apoptosis regulation in ovarian cancer allow the cancer cells to evade cell death and contribute to chemoresistance. Mcl-1 is an anti-apoptotic member of the Bcl-2 proteins family and its amplifıcation is one of the most frequent genetic aberrations found in human cancers. Its expression is at the origin of the acquired resistance to chemotherapy and to Bcl-2 and Bcl-xL inhibitors. In ovarian cancers, we previously demonstrated that Bcl-xL and Mcl-1 cooperate to prevent cancer cells from undergoing apoptotic cell death. Their concomitant inhibitions lead to massive apoptosis even in absence of chemotherapy. Moreover, in some cases, Mcl-1 inhibition is itself able to lead to apoptosis. If clinically relevant pharmacologic inhibition of Bcl-xL is available using ABT-263, selective direct inhibition of Mcl-1 remains problematic. In this context, our teams have designed and synthesized small compounds based on a pyridyl scaffold, named oligopyridines, which potentially target the Mcl-1 hydrophobic binding pocket. We demonstrated that the lead of the first generation of oligopyridines, named Pyridoclax, interacts directly with Mcl-1, releases its pro-apoptotic partners Bim and Bak and induces massive apoptosis at 25 µM concentration in combination with anti-Bcl-xL strategies in chemoresistant ovarian cancer cell lines (Gloaguen et al., J Med Chem 2015). In the present study, we investigated the antitumor activity of Pyridoclax hydrochloride in three subcutaneous xenograft models derived from the injection of chemoresistant ovarian cancer cell lines. Different routes of Pyridoclax hydrochloride administration were tested and its antitumor effect was analyzed at different doses as single agent or in combination with ABT-263. This study highlighted an effective antitumor activity of 20mg/kg of Pyridoclax administered intravenously as single agent in two of three xenograft models without side effects. In order to improve its biological activity, we evaluated the cytotoxic effects of a second generation of oligopyridines derived from the Pyridoclax. This allowed us to identify the MR31367, one of the most potent oligopyridines that shows a stronger pro-apoptotic activity in association with to Bcl-xL-targeting strategies in ovarian cancer cell lines. Further characterization showed that this derivative binds Mcl-1 and release Bim and Bak from it, leading to Bak-mediated apoptosis. Overall, these results open up interesting perspectives for the clinical use of Mcl-1 inhibitors as single agent or in combination with anticancer drugs to improve the clinical management of ovarian cancers. Citation Format: Siham Hedir, Louis-Bastien Weiswald, Marcella De Giorgi, Jade Fogha, Martina De Pascale, Emilie Brotin, Bogdan Marekha, Peggy Suzanne, Fabien Gautier, Philippe Juin, Laetitia Ligat, Frédéric Lopez, Rémi Legay, Ronan Bureau, Sylvain Rault, Jana Sopkova-de Oliveira Santos, Anne-Sophie Voisin-Chiret, Laurent Poulain. Pyridoclax and its derivatives from oligopyridine family directly inhibit Mcl-1 and exert potent antitumor effects on ovarian cancer in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3996.