Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC(50) < 500 nM. A critical selection process was then applied with two clusters and two singletons (1-4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/beta-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.
Steadman D, Atkinson BN, Zhao Y, Willis NJ, Frew S, Monaghan A, Patel C, Armstrong E, Costelloe K, Magno L, Bictash M, Jones EY, Fish PV, Svensson F (2022) Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity Journal of Medicinal Chemistry65: 562-578
Steadman D, Atkinson BN, Zhao Y, Willis NJ, Frew S, Monaghan A, Patel C, Armstrong E, Costelloe K, Magno L, Bictash M, Jones EY, Fish PV, Svensson F (2022) Journal of Medicinal Chemistry65: 562-578
