Discovery of Novel Bicyclic Pyrazoles as Potent PIP5K1C Inhibitors

Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) is generated by phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) from phosphatidylinositol 4-phosphate (PI4P). Structurally diverse and selective inhibitors against PIP5Ks are required to further elucidate the therapeutic potential for PIP5K inhibition, although the effects of PIP5K inhibition on various diseases and their symptoms, such as cancer and chronic pain, have been reported. Our medicinal chemistry efforts led to novel and potent PIP5K1C inhibitors. Compounds 30 and 33 not only showed potent activity but also demonstrated low total clearance in mice and high levels of kinase selectivity. These compounds might serve as tools to further elucidate the complex biology and therapeutic potential of PIP5K inhibition

A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression

This study describes RK-701, an inhibitor of histone methyltransferases G9a/GLP, as a promising therapeutic candidate for sickle cell disease and a universal role of BGLT3 lncRNA in fetal hemoglobin reactivation by chemical inducers including RK-701