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
  • 1. Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: [email protected].
  • 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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