Optimization of a DNA encoded library derived autotaxin inhibitor hit to a potent in vivo LPA lowering quinazolinone compound with a non‑zinc binding mode.

In recent years, lysophospholipase autotaxin (ATX) has emerged as an attractive target for treating a variety of human diseases, including inflammation, neurodegeneration, angiogenesis, cancer, ocular and fibrotic diseases, among others. Starting with the quinazolinone hit structure 1, which emerged from a DNA-encoded library screen, the potent, non-Zn2+ binding ATX inhibitor 31 with good overall physicochemical properties has been developed. This compound demonstrated a sustained reduction of lysophosphatidic acid (LPA) in an in vivo rat experiment, qualifying it as a proof-of-concept compound for further mechanistic studies.