Structure-guided design of pyridoclax derivatives based on Noxa / Mcl-1 interaction mode

• Published in: European journal of medicinal chemistry Vol. 159; pp. 357 - 380
• Main Authors: Hedir, Siham, De Giorgi, Marcella, Fogha, Jade, De Pascale, Martina, Weiswald, Louis-Bastien, Brotin, Emilie, Marekha, Bogdan, Denoyelle, Christophe, Denis, Camille, Suzanne, Peggy, Gautier, Fabien, Juin, Philippe, Ligat, Laetitia, Lopez, Frédéric, Carlier, Ludovic, Legay, Rémi, Bureau, Ronan, Rault, Sylvain, Poulain, Laurent, Oliveira Santos, Jana Sopková-de, Voisin-Chiret, Anne Sophie
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.11.2018; Elsevier
• Subjects: Cancer; Chemistry, Medicinal; Life Sciences; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; OVARIAN-CARCINOMA CELLS; SMALL-MOLECULE; DOWN-REGULATION; MCL-1 INHIBITORS; GENERAL FORCE-FIELD; BH3 MIMETIC ABT-737; ANTITUMOR-ACTIVITY; BCL-2 FAMILY; GENETIC ALGORITHM; RATIONAL DESIGN
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.10.003

Protein-protein interactions are attractive targets because they control numerous cellular processes. In oncology, apoptosis regulating Bcl-2 family proteins are of particular interest. Apoptotic cell death is controlled via PPIs between the anti-apoptotic proteins hydrophobic groove and the pro-apoptotic proteins BH3 domain. In ovarian carcinoma, it has been previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect tumor cells against apoptosis. Moreover, Mcl-1 is a key regulator of cancer cell survival and is a known resistance factor to Bcl-2/Bcl-xL pharmacological inhibitors making it an attractive therapeutic target. Here, using a structure-guided design from the oligopyridine lead Pyridoclax based on Noxa/Mcl-1 interaction we identified a new derivative, active at lower concentration as compared to Pyridoclax. This new derivative selectively binds to the Mcl-1 hydrophobic groove and releases Bak and Bim from Mcl-1 to induce cell death and sensitize cancer cells to Bcl-2/Bcl-xL targeting strategies. [Display omitted] •Apoptosis regulating Bcl-2 family proteins.•Mcl-1, key regulator of cancer cell survival and resistance factor to Bcl-2/Bcl-xL pharmacological inhibitors.•Structure-guided design from Pyridoclax based on Noxa/Mcl-1 interaction.