Synthesis and biological evaluation of FJ-809, a compound originally described as MIM1 and an inhibitor of the anti-apoptotic protein Mcl-1. (22nd April 2022)

• Record Type: Journal Article
• Authors: Justaud, Frédéric; Paysant, Hippolyte; Weiswald, Louis Bastien; Jebahi, Abdelghani; Jouanne, Marie; Elie, Nicolas; Voisin-Chiret, Anne Sophie; Roisnel, Thierry; Orione, Clément; Levoin, Nicolas; Poulain, Laurent; Grée, René
• Is Part Of: New journal of chemistry. Volume 46:Number 19(2022)
• Page Start: 9119
• Page End: 9127
• Publication Date: 2022-04-22
• Subjects: Chemistry -- Periodicals; Chimie -- Périodiques; 540
• DOI: 10.1039/d1nj05987d
• Languages: English
• ISSNs: 1144-0546

Abstract

Abstract : The development of inhibitors of anti-apoptotic proteins, such as Mcl-1, is currently a very active area in the field of cancer research. Abstract : The development of inhibitors of anti-apoptotic proteins, such as Mcl-1, is currently a very active area in the field of cancer research. One of the very first reported inhibitors of Mcl-1 was the MIM1 molecule, but we have recently demonstrated that the structure of this compound had to be revised from 2 to the derivative 1 (FJ-809 ). In this paper we first develop a strategy to unambiguously prepare molecules such as 1 with a thiazol-3(2 H )-yl)imino core, instead of the [2(3H)-thiazolylidene]hydrazine previously found in MIM1 (2 ). Next a series of biological studies have been performed on 1, using IGROV1-R10 ovarian cancer cells as models, and they have been complemented by fluorescence polarisation assays. These studies demonstrated that the new compound FJ-809 (1) was devoid of any significant activity on Mcl-1, in contrast to 2 . Then molecular modelling and molecular dynamics studies have been performed in order to elucidate the differences between FJ-809 and MIM1 in their interaction with the Mcl-1 protein.