2. Academic Validation
  3. Identification of a Chemical Probe for BLT2 Activation by Scaffold Hopping

Identification of a Chemical Probe for BLT2 Activation by Scaffold Hopping

  • J Med Chem. 2025 Jan 23;68(2):1195-1221. doi: 10.1021/acs.jmedchem.4c01617.
Victor Hernandez-Olmos 1,  Jan Heering 1,  Niklas Ildefeld 2,  Johanna H M Ehrler 2,  Alexander Kaps 2,  Rinusha Rajkumar 2,  Beatrice Marinescu 2,  Astrid Kaiser 2,  Igor Macinkovic 3,  Mohammed A F Elewa 3 4,  Mohamad Wessam Alnouri 5,  Lewis Elson 2 6,  Manfred Schubert-Zsilavecz 2,  Wiebke Kallenborn-Gerhardt 7,  Achim Schmidtko 7,  Susanne Müller 2 6,  Stefan Offermanns 5 8,  Dieter Steinhilber 1 2,  Andreas Weigert 3,  Ewgenij Proschak 1 2
Affiliations

Affiliations

  • 1 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, Frankfurt am Main 60596, Germany.
  • 2 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 3 Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt 60590, Germany.
  • 4 Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt.
  • 5 Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Ludwigstr. 43, Bad Nauheim 61231, Germany.
  • 6 Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt 60438, Germany.
  • 7 Institute of Pharmacology and Clinical Pharmacy, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 8 Center for Molecular Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.
PMID: 39803894 DOI: 10.1021/acs.jmedchem.4c01617
Abstract

The leukotriene B4 receptor 2 (BLT2) is a G-protein coupled receptor, which is endogenously activated by 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). BLT2 is gaining attention as a potential therapeutic target involved in various pathologies including diabetic wound healing, ophthalmic diseases, and colitis. However, validation of BLT2 as drug target requires chemical probes and pharmacological tools which will allow for application in vivo. In this work, we present the discovery of a novel chemical probe T-10430 for BLT2 agonism following a scaffold-hopping approach. T-10430 exhibits high potency, good selectivity profile, promising physicochemical and PK properties and can potentially serve as orally applicable pharmacological tool for validation of BLT2 as drug target. Using T-10430, we demonstrate the beneficial effect of BLT2 activation in mouse model of psoriasis.

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