The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole <b>20</b>, guided by structure-based drug design, identified <b>20z</b> as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine <b>8</b> gave acid <b>26</b>. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable <i>in vitro</i> ADME profiles.