When a fiber-optic intracore Bragg grating is subject to an appreciable strain gradient, its reflective spectrum will not only be shifted but also be distorted because of the chirp of the grating. We employed the J-matrix formalism to calculate the influence of different strain gradients on the reflective spectra of Bragg gratings and have undertaken experiments to test these calculations. The results of these experiments have confirmed that intracore Bragg gratings can be used to evaluate strain gradients and can be thought of as quasi-distributed strain sensors. This adds a new dimension to structural sensing, permitting measurements in any situation where strain gradients exist. It also provides a warning of any sensor/host debonding.

A new distributed strain sensing technique using a fiber optic Bragg grating has been developed and tested. This is the first 'true' distributed strain sensor, to the authors' knowledge, with a high spatial resolution of about 1 mm. Since gratings can be made with a length of tens of centimeters, this new fiber optic measurement technique could have broad applications to smart materials and structures where monitoring of a continuous strain profile over a length of millimeters to tens of centimeters is needed. In this paper three different demodulation approaches are reviewed indicating a trade-off between a relatively simple measurement process for selected types of strain profile and a more complete measurement process that is suitable for any strain profile. Experimental results with different approaches are presented.

A method of extracting the strain profile along a fiber Bragg grating from the intensity reflection spectrum is described. The procedure is based on a filter synthesis theory that relates the aperiodicity of a grating with its reflection spectrum. To illustrate the approach, we measured the strain profile near a hole in a plate and obtained a strain resolution of 80 micro. The spatial resolution depends on the strain gradient; i.e., the higher the gradient, the better the resolution. A resolution of 0.8 mm was achieved for a 5-mm grating with a gradient of 250 micro/mm.

Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.

In this letter, we describe the design, synthesis, and structure−activity relationship of 5-anilinopyrazolo [1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT S129 , a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft. KEYWORDS: CK2 kinase, pyrazolo[1,5-a]pyrimidine, matched molecular pair, oxetane T he serine/threonine protein kinase CK2, a tetrameric complex containing two catalytic (α or α′) and two regulatory (β) subunits, controls cell growth, proliferation, and evasion of apoptosis by phosphorylation of a range of substrates in critical cellular signaling pathways including PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) and Wnt (wingless type MMTV integration site family).1−3 Overexpression of the CK2α subunit correlates with tumor aggressiveness and disease severity in certain cancers, while compensatory increases in CK2α′ levels have been observed in response to RNAi treatment in mice.4,5 Several academic and industrial research groups have been actively engaged in developing small molecule inhibitors of CK2 to provide further pharmacological validation of the compelling in vitro and in vivo data amassed to date. 6 The recent discovery of CX-4945, a selective, orally available inhibitor of CK2 by researchers from Cylene, represents an important first step in evaluating the clinical potential of this novel target in man. 7 We have recently described the design of a series of conformationally constrained inhibitors of CK2 containing the pyrazolo[1,5-a]pyrimidine nucleus.8 Members of this series of compounds exhibited potent inhibition of the enzyme, possessed a high degree of kinase selectivity, and depleted cellular levels of pAKT S129 , a direct substrate of CK2 believed to hyperactivate the AKT pathway.9 Although our attempts to enhance both cellular potency and physical properties in this series were unsuccessful, these studies resulted in an understanding of the structure−property relationships within the scaffold and provided additional insights into ligand−receptor binding. In particular, we found that N-methylation of the acetamide of 1a, to give ring-constrained analogue 1b, preserved enzymatic and cellular activity. In subsequent designs, we proposed to release the constraint in 1b and introduce a new conformational constraint, exemplified by indoline 2, that would enforce the crystallographically observed cisoid conformation of the acetamide in 1 (Figure 1). Compound 2 is a potent inhibitor