WAY 316606

WAY 316606 is a selective small-molecule inhibitor of secreted frizzled-related protein-1 (sFRP-1) with EC50 value of 0.65 μM [1].
The Wnt signaling has been proved to be a drug target of treatment for metabolic bone diseases such as osteoporosis. The studies found that loss-of-function mutations of Wnt antagonists caused increased bone formation and deletion of the Wnt antagonist sFRP-1 resulted in increased trabecular bone formation in aged mice. Thus small-molecule inhibitors of Wnt antagonist (sFRP-1) have been discovered and developed. WAY 316606 was screened out from a library of over 440,000 compounds by the cell-based assay measuring activation of Wnt signaling. It bound to sFRP-1 preferentially (Kd value of 0.08 μM) and inhibited the negative regulation of Wnt caused by sFRP-1. WAY 316606 has been proved to promote bone formation in an organ culture assay [1].
WAY 316606 is a selective inhibitor of sFRP-1. It bound to sFRP-2 with 10-fold weaker affinity (Kd value of 1 μM). In a fluorescence polarization binding assay, WAY 316606 inhibited sFRP-1 with IC50 value of 0.5 μM. Although sequence of sFRP-1, -2 and -5 showed high identity, WAY 316606 selectively inhibited sFRP-1 against other two proteins. In the osteosarcoma U2-OS cell line used in a cell-based transient transfection and luciferase reporter assay, treatment of WAY 316606 dose-dependently increased Wnt-signaling with EC50 value of 0.65 μM. In an ex vivo assay using neonatal murine calvarium, treatment of WAY 316606 dose-dependently enhanced the osteoblast activity and stimulated bone formation up to 60% with EC50 value of 1 nM [1 and 2].
Although WAY 316606 had good aqueous solubility and good stability, WAY 316606 exerted high plasma clearance (77 mL/min/kg) in rats, which suppressed sustained exposure and limited the compound's advancement as an orally administered anabolic bone agent [1].
References:
[1] Bodine P V N, Stauffer B, Ponce-de-Leon H, et al. A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation. Bone, 2009, 44(6): 1063-1068.
[2] Moore W J, Kern J C, Bhat R, et al. Modulation of Wnt Signaling Through Inhibition of Secreted Frizzled-Related Protein I (sFRP-1) with N-Substituted Piperidinyl Diphenylsulfonyl Sulfonamides†. Journal of medicinal chemistry, 2008, 52(1): 105-116.

The problem of choice: From the voluntary way to Affordable Care Act health insurance exchanges.[Pubmed:28371627]

Soc Sci Med. 2017 May;181:34-42.

This article takes a genealogical and ethnographic approach to the problem of choice, arguing that what choice means has been reworked several times since health insurance first figured prominently in national debates about health reform. Whereas voluntary choice of doctor and hospital used to be framed as an American right, contemporary choice rhetoric includes consumer choice of insurance plan. Understanding who has deployed choice rhetoric and to what ends helps explain how offering choices has become the common sense justification for defending and preserving the exclusionary health care system in the United States. Four case studies derived from 180 enrollment observations at the Rhode Island health insurance exchange conducted from March 2014-January 2017 and interviews with enrollees show how choice is experienced in this latest iteration of health reform. The Affordable Care Act (ACA) of 2010 created new pathways to insurance coverage in the United States. Insurance exchanges were supposed to unleash the power of consumer decision-making through marketplaces where health plans compete on quality, coverage, and price. Consumers, however, contended with confusing insurance terminology and difficult to navigate websites. The ethnography shows that consumers experienced choice as confusing and overwhelming and did not feel "in charge" of their decisions. Instead, unstable employment, changes in income, existing health needs, and bureaucratic barriers shaped their "choices."

DNA Three-Way Junction for Differentiation of Single-Nucleotide Polymorphisms with Fluorescent Copper Nanoparticles.[Pubmed:28370648]

Chemistry. 2017 May 23;23(29):6979-6982.

A label- and enzyme-free fluorescent sensor for the detection of single-nucleotide polymorphisms (SNPs) at room temperature is proposed, using new copper nanoparticles (CuNPs) as fluorescent reporters. The CuNPs were constructed by using a DNA three-way junction (3WJ) template. In this assay, two complementary adenine/thymine-rich probes can hybridize with the wild-type target simultaneously to construct a 3WJ structure, serving as an efficient scaffold for the generation of CuNPs. However, the CuNPs produce weak fluorescence when the probes bind with a mutant-type target. SNPs can be identified by the difference in fluorescence intensity of the CuNPs. This SNPs detection strategy is straightforward, cost-effective, and avoids the complicated procedures of labeling or enzymatic reactions. The fluorescent sensor is versatile and can be applied to all types of mutation because the probes are programmable. Moreover, the sensor exhibits good detection performance in biological samples.

WAY 316606 is an inhibitor of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. The affinity of WAY-316606 for sFRP-1 is determined using the FP binding assay with IC50 of 0.5 μM.

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