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

Bioorg Med Chem Lett. 2025 Aug 1:123:130221. doi: 10.1016/j.bmcl.2025.130221. Epub 2025 Apr 5.

Abstract

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.

Keywords: Autotaxin inhibitor; DNA-encoded library (DEL); Enzyme; Lysophosphatidic acid (LPA); Lysophosphatidylcholine (LPC).

MeSH terms

  • Animals
  • Binding Sites
  • DNA* / chemistry
  • Dose-Response Relationship, Drug
  • Humans
  • Lysophospholipids* / antagonists & inhibitors
  • Lysophospholipids* / metabolism
  • Molecular Structure
  • Phosphodiesterase Inhibitors* / chemistry
  • Phosphodiesterase Inhibitors* / pharmacology
  • Phosphoric Diester Hydrolases* / metabolism
  • Quinazolinones* / chemical synthesis
  • Quinazolinones* / chemistry
  • Quinazolinones* / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Zinc / chemistry
  • Zinc / metabolism

Substances

  • alkylglycerophosphoethanolamine phosphodiesterase
  • Phosphoric Diester Hydrolases
  • Quinazolinones
  • Lysophospholipids
  • lysophosphatidic acid
  • DNA
  • Zinc
  • Phosphodiesterase Inhibitors