Synthesis and biological evaluation of FJ-809, a compound originally described as MIM1 and inhibitor of the anti-apoptotic protein Mcl-1

International audienceThe 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 inhibitor of Mcl-1 was the molecule MIM1, but we have demonstrated recently 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 prepare unambiguously molecules such as 1 with a thiazol-3(2H)-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, contrary to 2. Then molecular modelling and molecular dynamic studies have been performed in order to elucidate the differences between FJ-809 and MIM1 in their interaction with the Mcl-1 protein