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Design of selective PI3Kα inhibitors starting from a promiscuous pan kinase scaffold.

Starting from compound 1, a potent PI3Kα inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3Kα and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Kα, with excellent kinase selectivity.
Copyright © 2015 Elsevier Ltd. All rights reserved.

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Smac mimetic with TNF-α targets Pim-1 isoforms and reactive oxygen species production to abrogate transformation from blebbishields.

Cancer cells are capable of sphere formation (transformation) through reactive oxygen species (ROS) and glycolysis shift. Transformation is linked to tumorigenesis and therapy resistance, hence targeting regulators of ROS and glycolysis is important for cancer therapeutic candidates. Here, we demonstrate that Smac mimetic AZ58 in combination with tumour necrosis factor-α (TNF-α) was able to inhibit the production of ROS, inhibit glycolysis through Pim-1 kinase-mediated Ser-112 phosphorylation of BAD, and increase depolarization of mitochondria. We also identified mitochondrial isoforms of Pim-1 kinase that were targeted for degradation by AZ58 in combination with TNF-α or AZ58 in combination with Fas ligand (FasL) plus cycloheximide (CHX) through caspase-3 to block transformation. Our study demonstrates that Smac mimetic in combination with TNF-α is an ideal candidate to target Pim-1 expression, inhibit ROS production and to block transformation from blebbishields.
© 2016 Authors; published by Portland Press Limited.

Application of lentiviral vectors for development of production cell lines and safety testing of lentiviral-derived cells or products.

Lentiviral vectors (LVs) are frequently used to engineer cell lines for preclinical research purposes including assay development and target validation. Development of production cell lines for manufacturing recombinant protein therapeutics may also benefit from the use of LVs because they may reduce timelines and generate more uniform or higher expressing stable pools and clones. In addition, LVs could be advantageous for engineering new, alternative host cell substrates due to their ability to efficiently transduce most cell types. We demonstrate here that NS0 mouse myeloma cells, a host cell frequently used for protein production, can be transduced with LVs to greater than 80% efficiency and with no cytotoxic effects. The use of LVs for engineering of production cell lines will require additional testing procedures. Since LVs have previously been used in human gene therapy clinical trials, safety testing assays and procedures have been developed that could easily be applied to the development process for manufacturing cell lines to ensure the absence of unwanted viral material in cell banks and biologic products.

A biotech production facility contamination case study–minute mouse virus.

CONFERENCE PROCEEDING Proceedings of the PDA/FDA Adventitious Viruses in Biologics: Detection and Mitigation Strategies Workshop in Bethesda, MD, USA; December 1-3, 2010 Guest Editors: Arifa Khan (Bethesda, MD), Patricia Hughes (Bethesda, MD) and Michael Wiebe (San Francisco, CA).

Hypothesis testing for two-stage designs with over or under enrollment.

Simon’s two-stage designs are widely used in cancer phase II clinical trials for assessing the efficacy of a new treatment. However in practice, the actual sample size for the second stage is often different from the planned sample size, and the original inference procedure is no longer valid. Previous work on this problem has certain limitations in computation. In this paper, we attempt to maximize the unconditional power while controlling for the type I error for the modified second stage sample size. A normal approximation is used for computing the power, and the numerical results show that the approximation is accurate even under small sample sizes. The corresponding confidence intervals for the response rate are constructed by inverting the hypothesis test, and they have reasonable coverage while preserving the type I error.
Copyright © 2015 John Wiley &amp; Sons, Ltd.