Discovery of two small molecule inhibitors, ML387 and ML388, of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase

The central role of hydroxyprostaglandin dehydrogenase(HPGD) is to inactivate prostaglandins such as prostaglandin E₂ (PGE₂) or prostaglandin D₂ (PGD₂). These prostaglandins are involved in a number of processes, including inflammation, differentiation, and cellular signaling, which makes HPGD an important target for pharmacological intervention. High throughput screening of the Molecular Libraries Small Molecule Repository (MLSMR) led to the identification of three small molecule inhibitors of HPGD with differing mechanisms of action (ML147, ML148, and ML149). Herein, we report, the structure-activity relationship (SAR) studies, cell-based characterization and selectivity studies around the ML148 and ML149 scaffolds. These combined efforts led to the identification of two novel small molecule chemical probes (ML387 and ML388) with nanomolar inhibitory activity and excellent selectivity toward HPGD. Moreover, these compounds were shown to potently promote PGE₂ production in both A549 lung Cancer and LNCaP prostate Cancer cells. As part of these studies, we also profiled top compounds for select in vitro ADME properties to facilitate future optimization efforts.