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Highly selective anti-cancer properties of ester functionalized enantiopure dinuclear gold(I)-diphosphine.

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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Gating by tryptophan 73 exposes a cryptic pocket at the protein-binding interface of the oncogenic eIF4E protein.

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.

Noncanonical NF-κB Signaling in Health and Disease.

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.

6-K – Report of foreign issuer [Rules 13a-16 and 15d-16]

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:

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."

PharmaMar will be present at the 2016 Annual AACR Congress with the latest novelties in its compounds of marine origin in solid and hematological tumors

On April 14th, 2016 PharmaMar (MSE:PHM) reported that it will present the latest data obtained on its compounds of marine origin, lurbinectedin, plitidepsin and PM184 at the Annual Congress of the American Association of Cancer Research (AACR) (Free AACR Whitepaper), that will be held in New Orleans from the 16th to the 20th of April (Press release, PharmaMar, APR 14, 2016, View Source [SID:1234510765]). Under the heading "Delivering Cures Through Cancer Science", oncologists and investigators from around the world will interchange knowhow and reinforce the links between research and the advancements in patient care.

Through the studies that will be presented, PharmaMar will reveal the new results of its three molecules that are presently under clinical investigation in different types of solid and hematological tumors. Each one of these compounds has a very different mechanism of action. Apart from its direct activity on tumor cells, lurbinectedin (PM1183) also attacks the microenvironment, rendering tumor growth unfeasible. Plitidepsin (Aplidin), targets the eEF1A2 protein, and finally PM184 disrupts the tumor’s blood vessels, causing a reduction in the supply of both nutrients and oxygen to the tumor cells.
"In PharmaMar we have a commitment to the identification of new and novel mechanisms of action from marine compounds that can provide a step forward in the treatment of patients with cancer," explains Carmen Cuevas, Ph.D., R&D Director from the Oncology Business Unit at PharmaMar. "The results that we will present at scientific congresses such as the AACR (Free AACR Whitepaper) show that we are on right road and, that we can count on a robust pipeline that, without any doubt, will provide 2 new methods for attacking tumor cells."

Studies that will be presented at the 2016 AACR (Free AACR Whitepaper)
PM1183 (lurbinectedin) PM1183 is compound under clinical investigation, inhibitor of the RNA polymerase II enzyme. It is essential for the transcription process, inhibiting tumor growth, and resulting in tumor death. The antitumor efficacy of PM1183 is being investigated in various types of solid tumors.

Lurbinectedin reduces tumor-associated macrophages and the production of inflammatory cytokines, chemokines and angiogenic factors in preclinical models (abstract No 1284). Paola Allavena et al. Poster presentation, section 18, Monday April 18th, 8:00 am – 12:00 am.

This proves that part of lurbinectedin’s antitumor activity is due to its antiproliferative activity in monocytes and tumor associated macrophages, cells that are essential in the inflammatory microenvironment. Lurbinectedin inhibits transcription, therefore, the production of cytokines and angiogenic factors by these cells. Tumor growth is unfeasible, even when the tumor cells are resistant to the compound.

Lurbinectedin specifically targets transcription in cancer cells, triggering DNA breaks and degradation of phosphorylated Pol II (Abstract No 3039). Gema Santamaría-Nuñez et al. Poster presentation, section 17, Tuesday April 19th , 8:00 am-12:00 am.
Lurbinectedin (PM1183) binds to the DNA in the CG rich regions surrounding the promoter of genes, inhibiting transcription activity. The mechanism involves the ubiquitination and degradation by proteasome of the RNA polymerase II (pol II). The degradation of pol II is directly related to the appearance of DNA damage and the induction of cell death through apoptosis.
Plitidepsin (Aplidin) Plitidepsin is an antitumor drug of marine origin, at the investigational phase for hematological tumors, including a phase Ib study in relapsed and refractory Multiple Myeloma, in triple combination with bortezomib and dexamethasone, along with a phase II study in Relapsed and Refractory Angioimmunoblastic T-cell 3 Lymphoma. Recently, positive results have been seen in pivotal study in combination with dexamethasone in patients with Multiple Myeloma.

Plitidepsin targets the GTP-bound form of eEF1A2 in cancer cells (Abstract No 3015). Alejandro Losada et al. Poster presentation, section 17, Tuesday April 19th, 8:00am-12:00am.

This confirms that the protein eEF1A2 is Aplidin’s pharmacological target. This protein has numerous functions within the tumor cell, some of which have a marked oncogenic character. This assay delves into the peculiarities of the direct interaction of Aplidin with purified GTP bound eEF1A2.

PM184
PM184 is an inhibitor of tubulin polymerization. It is at the clinical development stage for solid tumors, including a Phase II trial in hormone-receptor positive, HER2-negative, locally advanced and/or metastatic breast cancer.

Anti-angiogenic properties of PM184 (Abstract No 3066). Carlos M. Galmarini et al. Poster presentation, section 25, Tuesday April 19th, 8:00am-12:00am.

The tumor cells rapidly growth, needing the supply of a large quantity of nutrients. One of the paths for the treatment of cancer at the moment is to disrupt the blood cells within the tumor, or to stop the development of new cells, cutting the supply of nutrients and oxygen to the tumor cells. Adding to its capacity to specifically eliminate tumor cells, PM184 has shown itself to have a strong intratumor vascular disrupting activity, inhibiting in this extraordinarily effective way, human transplanted tumors in mice.