Bcl-2 family proteins as therapeutic targets.
ABSTRACT The mitochondrion provides the stage for the interplay of molecular interactions that regulate apoptosis via the intrinsic pathway. The release of apoptogenic factors from this compartment constitutes a critical juncture in this apoptotic pathway. Regulation of the integrity of the outer mitochondrial membrane (OMM) is the task of the Bcl-2 family of proteins. A network of interactions between the various subgroups of the family decides the apoptotic fate of a cell and, as such, an imbalance within this network can lead to a variety of disease states. In particular, over-expression of pro-survival Bcl-2 family proteins is a hallmark of many cancers. Here we discuss recent advances in targeting the Bcl-2 family with both peptides and small molecules.
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ABSTRACT: Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionality, in silico design and X-ray crystallography were utilized to develop alternative scaffolds that retained the selectivity and potency of the starting compounds.ACS Medicinal Chemistry Letters 06/2014; 5(6):662-7. DOI:10.1021/ml500030p · 3.07 Impact Factor
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ABSTRACT: The BCL-2 protein family determines the commitment of cells to apoptosis, an ancient cell suicide programme that is essential for development, tissue homeostasis and immunity. Too little apoptosis can promote cancer and autoimmune diseases; too much apoptosis can augment ischaemic conditions and drive neurodegeneration. We discuss the biochemical, structural and genetic studies that have clarified how the interplay between members of the BCL-2 family on mitochondria sets the apoptotic threshold. These mechanistic insights into the functions of the BCL-2 family are illuminating the physiological control of apoptosis, the pathological consequences of its dysregulation and the promising search for novel cancer therapies that target the BCL-2 family.Nature Reviews Molecular Cell Biology 12/2013; 15(1):49-63. DOI:10.1038/nrm3722 · 36.46 Impact Factor
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ABSTRACT: The Bcl-2 family of proteins represents a compelling medicinal chemistry challenge. Despite the immense interest in developing compounds modulating apoptosis, only a few inhibitors have reached clinical trial. Potent molecules that afford new opportunities to treat cancers via reactivation of the cell death machinery are greatly needed. Herein, we describe the hit-to-lead development of selective Bcl-XL inhibitors originating from one molecule with low micromolar affinity for Bcl-XL discovered after a high-throughput screening campaign. Small changes to its structure resulted in more than three hundred-fold increase in binding affinity (IC50 < 20 nM). This series of small molecules exhibits drug-like characteristics and retain low molecular weights (Mw < 450). Importantly, these molecules exhibit unprecedented selectivity for Bcl-XL. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-XL. Combined results obtained in biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEF, relying only on Bcl-XL for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of the Bcl-2-driven apoptotic cascade) support a mechanism-based induction of apoptosis. In summary, this research describes the first series of small-molecule selective inhibitors of Bcl-XL and provides promising leads for the future development of efficacious therapeutics against solid tumours and chemo-resistant cancer cell lines.Journal of Medicinal Chemistry 06/2013; 56(13):5514–5540. DOI:10.1021/jm400556w · 5.48 Impact Factor