ABT-199 is a specific Bcl-2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co-expression of Mcl-1 and Bcl-xL.
Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway.
Members of MCL1-M captured both MM cell-intrinsically acting signals and the signals regulating the interaction between MM cells with bone marrow microenvironment.
In conclusion, the NEAT1/miR-193a/MCL1 pathway is closely associated with the development of DEX resistance in myeloma cells, and knockdown of NEAT1 can significantly improve DEX sensitivity in MM.
This work led to the discovery of <b>1</b>, a potent Mcl-1 inhibitor (IC<sub>50</sub> = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.
Co-culture experiments resulted in MDSC-induced AMPK phosphorylation in MM cells, which was associated with an increase in the anti-apoptotic factors MCL-1 and BCL-2, and the autophagy-marker LC3II.