KY 02111

KY 02111 is a selective inhibitor of Wnt may by targeting the downstream from GSK3βand APC in β-catenin destruction complex [1].

Wnt signaling pathways are a group of signal transduction pathways made of proteins and play an important role in passing signals from outside of a cell through cell surface receptors to the inside of the cell. Wnt signaling initially was identified as a pivotal mediator in carcinogenesis, but has since been recognized for its function in embryonic development, including body axis patterning, cell fate specification, cell proliferation, and cell migration which are necessary for proper formation of important tissues including bone, heart, and muscle [2].

KY 02111 is a potent Wnt inhibitor and has a different selectivity with the reported Wnt inhibitors. When tested with IMR90-1 hiPSCs transfected with TCF receptor plasmids, KY 02111 (1 μM) significantly reduced luciferase activities in a dose-dependent manner by inhibiting canonical WNT signaling pathway. In cardiac colonies on the day 30, KY 02111 showed that nearly 73%-85% of IMR90-1 hiPSCs expressed the cardiac markers [1].

References:
[1].  Minami, I., et al., A small molecule that promotes cardiac differentiation of human pluripotent stem cells under defined, cytokine- and xeno-free conditions. Cell Rep, 2012. 2(5): p. 1448-60.
[2].  Stamatakou, E., M. Hoyos-Flight, and P.C. Salinas, Wnt Signalling Promotes Actin Dynamics during Axon Remodelling through the Actin-Binding Protein Eps8. PLoS One, 2015. 10(8): p. e0134976.

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency.[Pubmed:27485408]

Eur J Hum Genet. 2016 Dec;24(12):1771-1777.

We describe a new early-onset neuromuscular disorder due to a homozygous loss-of-function variant in the kyphoscoliosis peptidase gene (KY). A 7.5-year-old girl with walking difficulties from 2 years of age presented with generalized muscle weakness; mild contractures in the shoulders, hips and feet; cavus feet; and lordosis but no scoliosis. She had previously been operated with Achilles tendon elongation. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Biopsy of the vastus lateralis muscle showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c.1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel showed that KY is predominantly expressed in skeletal muscle in humans. A recessive variant in the murine ortholog Ky was previously described in a spontaneously generated mouse mutant with kyphoscoliosis, which developed postnatally and was caused by dystrophy of postural muscles. The abnormal distribution of Xin and Ky-binding partner filamin C in the muscle fibers of our patient was highly similar to their altered localization in ky/ky mouse muscle fibers. We describe the first human case of disease associated with KY inactivation. As in the mouse model, the affected child showed a neuromuscular disorder - but in contrast, no kyphoscoliosis.

A small molecule that promotes cardiac differentiation of human pluripotent stem cells under defined, cytokine- and xeno-free conditions.[Pubmed:23103164]

Cell Rep. 2012 Nov 29;2(5):1448-60.

Human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, are potentially useful in regenerative therapies for heart disease. For medical applications, clinical-grade cardiac cells must be produced from hPSCs in a defined, cost-effective manner. Cell-based screening led to the discovery of KY02111, a small molecule that promotes differentiation of hPSCs to cardiomyocytes. Although the direct target of KY02111 remains unknown, results of the present study suggest that KY02111 promotes differentiation by inhibiting WNT signaling in hPSCs but in a manner that is distinct from that of previously studied WNT inhibitors. Combined use of KY02111 and WNT signaling modulators produced robust cardiac differentiation of hPSCs in a xeno-free, defined medium, devoid of serum and any kind of recombinant cytokines and hormones, such as BMP4, Activin A, or insulin. The methodology has potential as a means for the practical production of human cardiomyocytes for regeneration therapies.