Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors

Blockade of aberrant Wnt signaling is an attractive therapeutic approach in multiple cancers. We developed and performed a cellular high-throughput screen for inhibitors of Wnt secretion and pathway activation. A lead structure (GNF-1331) was identified from the screen. Further studies identified the molecular target of GNF-1331 as Porcupine, a membrane bound O-acyl transferase. Structure–activity relationship studies led to the discovery of a novel series of potent and selective Porcupine inhibitors. Compound <b>19</b>, GNF-6231, demonstrated excellent pathway inhibition and induced robust antitumor efficacy in a mouse MMTV-WNT1 xenograft tumor model

Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator

A novel series of alkoxyimino derivatives as S1P₁ agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure–activity relationship studies led to the discovery of (<i>E</i>)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)­benzyl)­oxy)­imino)­ethyl)-2-ethylbenzyl)­azetidine-3-carboxylic acid (<b>32</b>, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing–remitting multiple sclerosis