A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation

Like Bcl-2, Mcl-1 is an important survival factor for many cancers, its expression contributing to chemoresistance and disease relapse. However, unlike other prosurvival Bcl-2–like proteins, Mcl-1 stability is acutely regulated. For example, the Bcl-2 homology 3 (BH3)–only protein Noxa, which preferentially binds to Mcl-1, also targets it for proteasomal degradation. In this paper, we describe the discovery and characterization of a novel BH3-like ligand derived from Bim, BimS2A, which is highly selective for Mcl-1. Unlike Noxa, BimS2A is unable to trigger Mcl-1 degradation, yet, like Noxa, BimS2A promotes cell killing only when Bcl-xL is absent or neutralized. Furthermore, killing by endogenous Bim is not associated with Mcl-1 degradation. Thus, functional inactivation of Mcl-1 does not always require its elimination. Rather, it can be efficiently antagonized by a BH3-like ligand tightly engaging its binding groove, which is confirmed here with a structural study. Our data have important implications for the discovery of compounds that might kill cells whose survival depends on Mcl-1

VDAC2 enables BAX to mediate apoptosis and limit tumor development

BAX and BAK are pro-apoptotic proteins whose activity is essential for the action of many anti-cancer drugs and to suppress tumorigenesis. Here, the authors perform a genome-wide CRISPR/Cas9 screen and identify VDAC2 as a promoter of BAX-mediated apoptosis that is important for an efficient chemotherapeutic response and to suppress tumor formation

The Dendritic Cell Receptor Clec9A Binds Damaged Cells via Exposed Actin Filaments

10.1016/j.immuni.2012.03.009Immunity364646-657IUNI

Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl‑X_L

Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-X_L inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC₅₀ < 20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (<i>M</i>_w < 450), and unprecedented selectivity for Bcl-X_L. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-X_L. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-X_L for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-X_L and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines