Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened

Inhibitors of the Hedgehog signaling pathway have generated a great deal of interest in the oncology area due to the mounting evidence of their potential to provide promising therapeutic options for patients. Herein, we describe the discovery strategy to overcome the issues inherent in lead structure <b>1</b> that resulted in the identification of Smoothened inhibitor 1-((2<i>R</i>,4<i>R</i>)-2-(1<i>H</i>-benzo­[<i>d</i>]­imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)­urea (PF-04449913, <b>26</b>), which has been advanced to human clinical studies

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with <i>in vivo</i>-active tool compound <b>EPZ015666</b> (<b>GSK3235025</b>) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor <i>in vitro</i> clearance to yield <i>in vivo</i> tool compound <b>EPZ015666</b> and an additional potent <i>in vitro</i> tool molecule <b>EPZ015866</b> (<b>GSK3203591</b>)