Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.
"Selective targeting of Mcl-1 has proven to be challenging relative to other Bcl-2 family members and may be attributable to the structure of Mcl-1 . A few selective Mcl-1 inhibitors are in preclinical development , such as the stapled peptide SAHB , the small molecules MIM1 , EU-5148 , and the compound 53 , as well as a novel class of hydroxynapthalen aryl sulfonamides . More recently, a small molecule inhibitor of Mcl-1, designated UMI77, that engages Mcl-1 at its canonical BH3-binding groove, was shown to have single agent activity in human pancreatic cancer models both in vitro and in vivo . "
"On the other hand, ABT-199 selectively targets Bcl-2 over Bcl-xL and other anti-apoptotic Bcl-2 members , while WEHI-539  and BXI-72  demonstrate high potency and specificity for Bcl-xL. Some selective Mcl-1 inhibitors have also been recently reported . Among highly potent and specific small-molecule inhibitors targeting these anti-apoptotic Bcl-2 proteins, ABT-263 ,  and ABT-199  have been advanced into clinical development and both compounds have demonstrated impressive antitumor activity as single agents in patients with chronic lymphocytic leukemia, in which the cells are primarily dependent upon Bcl-2 for survival. "
[Show abstract][Hide abstract] ABSTRACT: Bcl-2 and Bcl-xL are critical regulators of apoptosis that are overexpressed in a variety of human cancers and pharmacological inhibition of Bcl-2 and Bcl-xL represents a promising strategy for cancer treatment. Using a structure-based design approach, we have designed BM-1197 as a potent and efficacious dual inhibitor of Bcl-2 and Bcl-xL. BM-1197 binds to Bcl-2 and Bcl-xL proteins with Ki values less than 1 nM and shows >1,000-fold selectivity over Mcl-1. Mechanistic studies performed in the Mcl-1 knockout mouse embryonic fibroblast (MEF) cells revealed that BM-1197 potently disassociates the heterodimeric interactions between anti-apoptotic and pro-apoptotic Bcl-2 family proteins, concomitant with conformational changes in Bax protein, loss of mitochondrial membrane potential and subsequent cytochrome c release to the cytosol, leading to activation of the caspase cascade and apoptosis. BM-1197 exerts potent growth-inhibitory activity in 7 of 12 small cell lung cancer cell lines tested and induces mechanism-based apoptotic cell death. When intravenously administered at daily or weekly in H146 and H1963 small-cell lung cancer xenograft models, it achieves complete and long-term tumor regression. Consistent with its targeting of Bcl-xL, BM-1197 causes transit platelet reduction in mice. Collectively, our data indicate that BM-1197 is a promising dual Bcl-2/Bcl-xL inhibitor which warrants further investigation as a new anticancer drug.
PLoS ONE 06/2014; 9(6):e99404. DOI:10.1371/journal.pone.0099404 · 3.23 Impact Factor
"In contrast, a recent comparison of MCL-1 inhibitors showed that MIM-1 induced apoptosis only weakly at very high concentration (Varadarajan et al., 2013), suggesting that other pathways may be involved in its activity in other cell lines. More recently, a team at Vanderbilt University reported a novel MCL-1 inhibitor discovered through NMR-based fragment screening (Figure 4G; Friberg et al., 2013). Stephen Fesik, a member of this team, was one of the inventors of the 'SAR by NMR' technique that led to the discovery of ABT-737 (Petros et al., 2006). "
[Show abstract][Hide abstract] 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.
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