Optimization of Novel Pyrido-pyridazinone Derivatives as FER Tyrosine Kinase Inhibitors, Leading to the Potent DS08701581.

Previously, we reported the new pyrido-pyridazinone template as a feline sarcoma-related (FER) tyrosine kinase inhibitor. Representative compound () showed strong enzyme inhibitory activity (IC50 = 0.5 nM), however, its antitumor effect was insufficient, probably due to poor solubility and resultant low bioavailability (BA).

Novel protein kinase cAMP-Activated Catalytic Subunit Alpha (PRKACA) inhibitor shows anti-tumor activity in a fibrolamellar hepatocellular carcinoma model.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is known as a highly aggressive liver cancer that typically affects young adults without virus infection. Since this type of cancer does not respond to chemotherapy, surgery is the only known effective therapeutic option. Most FL-HCC patients express the fusion gene DNAJB1-PRKACA, which has been recognized as the signature of FL-HCC.

Regeneration in Experimental Alveolar Bone Defect Using Human Umbilical Cord Mesenchymal Stem Cells.

Cleft lip and palate is a congenital disorder including cleft lip, and/or cleft palate, and/or alveolar cleft, with high incidence.The alveolar cleft causes morphological and functional abnormalities. To obtain bone bridge formation and continuous structure between alveolar clefts, surgical interventions are performed from infancy to childhood.

Discovery of Novel Pyrido-pyridazinone Derivatives as FER Tyrosine Kinase Inhibitors with Antitumor Activity.

To obtain a new anticancer drug, we focused on FER tyrosine kinase. Starting with high-throughput screening with our in-house chemical library, compound , which has a pyridine moiety, was found. Referring to their X-ray crystal structure with FES proto-oncogene tyrosine kinase, as a surrogate of FER followed by chemical modification including scaffold hopping of the pyridine template, we discovered pyrido-pyridazinone derivatives with potent FER kinase inhibitory activity.

Stress fracture of the thoracic spine in an elite rhythmic gymnast: A case report.

Spondylolysis, a defect or stress fracture of the vertebral pars interarticularis, occurs most frequently in the lower lumbar spine and occasionally in the cervical spine, but is extremely rare in the thoracic spine. We report the case of a 17 year-old girl, an elite rhythmic gymnast, who reported with early-stage thoracic spondylolysis at T10 and T11 levels. Physicians should be aware that performance of unusual athletic movements, such as those by gymnasts, may lead to spondylolysis in rare locations.