Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

Abstract Purpose: This study was designed to evaluate the potential of eFT508 to selectively regulate key immune signaling pathways and enhance anti-tumor immunity as a monotherapy or in combination with checkpoint blockade in immunocompetent syngeneic cancer models. Methods: eFT508 and its effect on mRNA translation, effector protein production, immune cell signaling and tumor infiltrating lymphocytes was evaluated in vitro using normal human T cells and in vivo utilizing immunocompetent syngeneic models. The mechanism of translational regulation of specific target genes was further evaluated in these model systems. Results: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors and hematological malignancies. MNK1 and MNK2 integrate signals from several oncogenic and immune signaling pathways (including RAS, p38 and toll-like receptors) by phosphorylating eukaryotic initiation factor 4E (eIF4E) and other key effector proteins including hnRNPA1 and PSF. Phosphorylation of these RNA-binding proteins by MNK1 and MNK2 selectively regulates the stability and translation of a subset of cellular mRNA that control tumor/stromal cell signaling and the tumor microenvironment. eFT508 inhibits both MNK1 and MNK2 through a reversible, ATP-competitive mechanism of action with an IC50 of 2 and 1 nM against MNK1 and MNK2 respectively. eFT508 is highly selective (≥100-fold) for MNK1 and MNK2 relative to over 400 other protein and lipid kinases. Ribosome profiling has demonstrated that inhibition of MNK1 and MNK2 by eFT508 selectively regulates the translational efficiency and mRNA stability of a subset of genes that include inflammatory cytokines/chemokines, regulators of reactive oxygen species (ROS), and effectors of anti-tumor immune response. Given the importance of both RAS signaling and translational control to immune cell function the immunological effect of eFT508 was evaluated in both normal human T cells in vitro and immunocompetent syngeneic cancer models in vivo. eFT508 treatment of normal donor T cells has no deleterious effect on CD3/CD28 activation of IL-2 production, T cell proliferation or on T cell viability. However, eFT508 selectively down regulates the induction of IL-10 and specific immune checkpoint mechanisms. The effect of eFT508 on IL-10 protein production corresponded with reduced mRNA stability. The in vivo antitumor effect of eFT508 was assessed in the CT26 BALB/C syngeneic tumor model. CT26 mouse tumor cell proliferation and survival are insensitive to eFT508 in vitro. In vivo, daily oral treatment with 1 mg/kg eFT508 results in significant anti-tumor activity and establishment of immune memory. In addition, combination of daily oral treatment of 1 mg/kg eFT508 with either anti-PD-1 or anti-PD-L1 monoclonal antibodies increases the number of responder animals and results in synergistic activity that corresponds to the modulation of tumor infiltrating lymphocyte populations. Conclusions: eFT508 is a selective, orally bioavailable small molecule inhibitor of MNK1 and MNK2 that can decrease the production of key immune checkpoint regulators and immunosuppressive cytokines. This novel mechanism of action triggers anti-tumor immune response in immunocompetent syngeneic animal models as a monotherapy and in combination with established immune checkpoint antibodies. eFT508 is currently under evaluation in two phase I clinical trials for patients with advanced solid tumors and patients with advanced lymphoma respectively. These findings support further clinical evaluation of eFT508 in combination with checkpoint blockade. This abstract is also being presented as Poster B29. Citation Format: Kevin R. Webster, Vikas K. Goel, Jocelyn Staunton, Ivy NJ Hung, Gregory S. Parker, Craig R. Stumpf, Jolene Molter, Gary G. Chiang, Christopher J. Wegerski, Samuel Sperry, Joan Chen, Vera Huang, Peggy A. Thompson, Chinh Tran, Justin T. Ernst, Stephen E. Webber, Paul A. Sprengeler, Siegfried H. Reich. eFT508: An oral, potent and highly selective inhibitor of MNK1 and MNK2, promotes anti-tumor immunity as a monotherapy and in combination with immune checkpoint blockade. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr PR11.

Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors and hematological malignancies. MNK1 and MNK2 integrate signals from several oncogenic and immune signaling pathways, including RAS, p38, and Toll-like receptor (TLR) pathways, by phosphorylating eukaryotic initiation factor 4E (eIF4E) and other key effector proteins including hnRNPA1 and PSF. Through phosphorylation of these regulatory proteins MNK1 and MNK2 selectively regulate the stability and translation of a subset of cellular mRNA. eFT508 is a potent, highly selective, and orally bioavailable MNK1 and MNK2 inhibitor. eFT508 has a half-maximal inhibitory concentration (IC50) of 1-2 nM against both MNK isoforms in enzyme assays and inhibits the kinase through a reversible, ATP-competitive mechanism of action. Treatment of tumor cell lines with eFT508 led to a dose-dependent reduction in eIF4E phosphorylation at serine 209 (IC50 = 2-16 nM), consistent with previous findings that phosphorylation of this site is solely dependent upon MNK1/MNK2. In a panel of ~50 hematological cancers, eFT508 showed anti-proliferative activity against multiple DLBCL cell lines. Sensitivity to eFT508 in TMD8, OCI-Ly3 and HBL1 DLBCL cell lines was associated with dose-dependent decreases in production of pro-inflammatory cytokines including TNFα, IL-6, IL-10 and CXCL10. Further evaluation eFT508 mechanism of action demonstrated that decreased TNFα production correlated with a 2-fold decrease in TNFα mRNA half-life. These findings are consistent with MNK1 phosphorylation of specific RNA-binding proteins, eg, hnRNPA1, that regulate the stability and translation of mRNA containing specific AU-rich elements (ARE) in their 3'-untranslated regions (UTR). Pro-inflammatory cytokines are drivers of key hallmarks of cancer including tumor cell survival, migration and invasion, angiogenesis, and immune evasion, while also driving drug resistance. Therefore, eFT508 was tested in vivo in 7 subcutaneous human lymphoma xenograft models. Significant anti-tumor activity was observed in the TMD8 and HBL-1 ABC-DLBCL models, both of which harbor activating MyD88 mutations. In addition, eFT508 combined effectively with components of R-CHOP and with novel targeted agents, including ibrutinib and venetoclax, in human lymphoma models. These results underscore the potential of eFT508 for the treatment of DLBCL. eFT508 has also been characterized in nonclinical safety pharmacology and toxicology studies. Clinical trials in patients with hematological and other malignancies are planned.

Questions the existence of traditionally‐structured organizations. Discusses important factors in successful organizations in a turbulent environment. Covers topics such as new challenges, new skills and virtual organizations.

Raiseboring is an attractive method of constructing shafts. However in the gravels and weathered near-surface rocks typical of the Western Australian goldfields, back reaming large diameter shafts through to the surface is risky, and conventional sinking from surface has normally been required.An alternative construction approach has recently been used to stabilise the weak surficial materials and allow raiseboring through to the surface. The method is based on installing rings of non-contiguous reinforced bored piles around the shaft perimeter, for temporary support, then back reaming shafts at full diameter, and then supporting the weak exposed materials using remotely sprayed fibrecrete.The method has been successfully applied to four shafts of 3 to 4·5 m diameter since July 2007. Bored pile layout designs have varied from 8 to 24 piles, of diameters 120–270 mm, in one or two rings. The practical implementation of the method was not always easy and many valuable lessons have been learnt.

Much of the literature on career management in the 1990s has been based on the assumption that a significant consequence of company restructuring has been the diminution of management career opportunities. Many human resource commentators are suggesting that the responsibility for managing and developing careers has become much more a personal quest and much less of an organisational one. This article examines the issues involved in managing careers from both perspectives and it uses primary research to illustrate and evaluate the range of activities currently being undertaken.

We present Illuminator, a user-friendly web front end to computational models such as docking and 3D shape similarity calculations. Illuminator was specifically created to allow non-experts to design and submit molecules to computational chemistry programs. As such it provides a simple user interface allowing users to submit jobs starting from a 2D structure. The models provided are pre-optimized by computational chemists for each specific target. We provide an example of how Illuminator was used to prioritize the design of molecular substituents in the Anadys HCV Polymerase (NS5B) project. With 7500 submitted jobs in 1.5 years, Illuminator has allowed project teams at Anadys to accelerate the optimization of novel leads. It has also improved communication between project members and increased demand for computational drug discovery tools.

This paper relates evidence obtained from an in-depth study involving detailed questioning of over 250 executives, during the period from 2000-2006, into the successes and challenges that those involved in KTP were experiencing. The analysis subsequently uncovered four fundamental themes (the 4 'C's of KTP) that will provide effective guidance to any future KTP, and more importantly, those responsible for them. The four themes outlined were Confusion, (what is KTP all about?), Convergence (how does the KTP fit with organizational or business strategy?), Commitment (how much time, effort and resources do we put to the KTP?) and finally Culture, how does KTP activity fit with and ultimately change the culture of the organisation?

The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.