Shannon M. Matulis

TL;DR: AZD5991 is a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

TL;DR: Analysis of Mcl-1-dependent multiple myeloma cell lines revealed codependence on Bcl-2/Bcl-x(L) in half the cells tested, and acquired resistance to ABT-737 results in loss of codependence through redistribution of Bim to M cl-1.

TL;DR: Combining this novel therapeutic with Dex could be an effective therapy for a broader range of patients than would be predicted by single-agent activity, and knowledge of drug-induced alterations of Bim-binding patterns may help inform better combination drug regimens.

TL;DR: Investigation revealed that cells surviving glutamine withdrawal in particular, enhance expression and binding of BIM to BCL-2, consequently sensitizing these cells to the BH3 mimetic venetoclax, revealing a potent therapeutic strategy of metabolically driven synthetic lethality involving targeting glutamine metabolism for sensitization to venetClax in MM.

TL;DR: It is shown that MLN4924, a potent NEDD8 activating enzyme (NAE) inhibitor, induced cytotoxicity in MM cell lines, and its antitumor effect is associated with suppression of the AKT and mammalian target of rapamycin signaling pathways through increased expression of REDD1.