BCL2 blunts activation of the mitochondrial pathway to apoptosis and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase I first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within four hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20mg or 50mg dose in some patients. The extent of mitochondrial depolarisation by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, while the LC50derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p,TP53mutation and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients, and support further assessment of BH3 profiling as a predictive biomarker for this drug.
Copyright © 2016 American Society of Hematology (ASH) (Free ASH Whitepaper).

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Two chiral (-)-diphosphine-digold(I) complexes containing mono- and di-methylester substituted diphosphine ligands have been prepared and structurally characterized. Both complexes are highly potent against breast cancer cell line MDA-MB-231 but showed much lower cytotoxicity against the normal human breast epithelial cells MCF10A. When compared with its mono-substituted analogue, the di-methylester substituted complex caused markedly lower and relatively insignificant damage to the normal breast cells. The analogous mono- and di-ethylester substituted complexes with the same stereochemistry exhibited similar anti-cancer properties but with noticeably higher cytotoxicity against the MCF10A cells. The enantiomeric complex (+)-diphosphine-digold(I) complexes containing the di-methylester substituted diphosphine ligand exhibited clearly different biological properties from its (-)-enantiomer. Furthermore, a structurally similar diphosphine-digold(I) complex but in the absence of an ester substituent, killed both the cancerous and the healthy cells indiscriminately. The current study thus revealed that the introduction of multi-esters, particularly methylesters, is an efficient approach to suppress the side-effects and to improve the efficiency of potential gold-based anti-cancer reagents. When combined with the biological observations, the chirality of gold complexes may serve as a sensitive probe for the future mechanistic studies.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.

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Targeting protein-protein interacting sites for potential therapeutic applications is a challenge in the development of inhibitors, and this becomes more difficult when these interfaces are relatively planar, as in the eukaryotic translation initiation factor 4E (eIF4E) protein. eIF4E is an oncogene that is overexpressed in numerous forms of cancer, making it a prime target as a therapeutic molecule. We report here the presence of a cryptic pocket at the protein-binding interface of eIF4E, which opens transiently during molecular dynamics simulations of the protein in solvent water and is observed to be stable when solvent water is mixed with benzene molecules. This pocket can also be seen in the ensemble of structures available from the solution-state conformations of eIF4E. The accessibility of the pocket is gated by the side-chain transitions of an evolutionarily conserved tryptophan residue. It is found to be feasible for accommodating clusters of benzene molecules, which signify the plasticity and ligandability of the pocket. We also observe that the newly formed cavity provides a favorable binding environment for interaction of a well-recognized small molecule inhibitor of eIF4E. The occurrence of this transiently accessible cavity highlights the existence of a more pronounced binding groove in a region that has traditionally been considered to be planar. Together, the data suggest that an alternate binding cavity exists on eIF4E and could be exploited for the rational design and development of a new class of lead compounds against the protein.

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Noncanonical NF-κB signaling differs from canonical NF-κB signaling by being activated through different cell surface receptors, cytoplasmic adaptors, and NF-κB dimers. Under normal physiological conditions, this noncanonical pathway has been implicated in diverse biological processes, including lymphoid organogenesis, B cell maturation, osteoclast differentiation, and various functions of other immune cells. Recently, dysfunction of this pathway has also been causally associated with numerous immune-mediated pathologies and human malignancies. Here, we summarize the core elements as well as the recently identified novel regulators of the noncanonical NF-κB signaling pathway. The involvement of this pathway in different pathologies and the potential therapeutic options that are currently envisaged are also discussed.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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On April 14, 2016 Trillium Therapeutics Inc. (Nasdaq:TRIL; TSX: TR) an immuno-oncology company developing innovative therapies for the treatment of cancer, reported it will be providing an update on its SIRPaFc immune checkpoint inhibitor program, targeting the CD47 protein, at the 107th Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Filing, 6-K, Trillium Therapeutics, APR 14, 2016, View Source [SID:1234510766]). The meeting will be held April 16-20, 2016 in New Orleans, LA. Details of the poster presentation, entitled "SIRPαFc, a CD47-Blocking Cancer Immunotherapeutic, Triggers Phagocytosis of Lymphoma Cells by Both Classically (M1) and Alternatively (M2) Activated Macrophages", are listed below:

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Date: Monday April 18, 2016
Time: 1:00 pm – 5:00 pm (CT)
Session Category: Immunology
Session Title: Immune Checkpoints 1
Abstract #: 2345
Presenter: Dr. Natasja Nielsen Viller
Location: Section 26

The company will present data demonstrating that its SIRPaFc fusion protein, which targets the CD47 "do not eat" signal, promotes the phagocytosis of lymphoma cells by diverse types of macrophages. The studies also assess the impact of macrophage polarizing agents on drug activity and delineate the role of different Fc gamma receptors in promoting tumor cell killing by SIRPaFc.

"Macrophages are heterogeneous and certain types, notably M2s, are often implicated in tumor progression," commented Trillium’s Chief Scientific Officer, Dr. Robert Uger. "Our data indicate that TTI-621, our CD47-blocking decoy receptor, enables all macrophage subsets tested, including M2s, to kill tumor cells. These results suggest that TTI-621 is able to convert otherwise pro-tumor macrophages into efficient anti-tumor effector cells. Rather than ablating M2 macrophages in the tumor microenvironment, these data support using TTI-621 to unleash their tumoricidal function."