2. Academic Validation
  3. 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

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.
Rainer E Martin 1,  Alexander L Satz 2,  Christoph Kuratli 2,  Daniel Hunziker 2,  Patrizio Mattei 2,  Jérôme Hert 2,  Christoph Ullmer 2,  Markus G Rudolph 2,  André M Alker 2,  Remo Hochstrasser 2,  Andreas Marx 2,  Martin Binder 2,  Stephan Müller 2
Affiliations

Affiliations

  • 1 Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: rainer_e.martin@roche.com.
  • 2 Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
PMID: 40194669 DOI: 10.1016/j.bmcl.2025.130221
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).

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