2. Academic Validation
  3. Discovery and Development of First-in-Class ACKR3/CXCR7 Superagonists for Platelet Degranulation Modulation

Discovery and Development of First-in-Class ACKR3/CXCR7 Superagonists for Platelet Degranulation Modulation

  • J Med Chem. 2022 Oct 13;65(19):13365-13384. doi: 10.1021/acs.jmedchem.2c01198.
Alp Bayrak 1,  Florian Mohr 1,  Kyra Kolb 2,  Martyna Szpakowska 3,  Ekaterina Shevchenko 4,  Valerie Dicenta 2,  Anne-Katrin Rohlfing 2,  Mark Kudolo 1,  Tatu Pantsar 1 5,  Marcel Günther 1,  Agnieszka A Kaczor 5 6,  Antti Poso 5 4,  Andy Chevigné 3,  Thanigaimalai Pillaiyar 1,  Meinrad Gawaz 2,  Stefan A Laufer 1
Affiliations

Affiliations

  • 1 Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 2 Department of Internal Medicine III, Cardiology and Angiology, University Hospital Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany.
  • 3 Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health (LIH), L-4354 Esch-sur-Alzette, Luxembourg.
  • 4 Department of Internal Medicine VIII, Oncology and Pneumology, University Hospital Tübingen, Otfried-Müller-Strasse 14, 72076 Tübingen, Germany.
  • 5 School of Pharmacy, University of Eastern Finland, P.O. BOX 1627, 70211 Kuopio, Finland.
  • 6 Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
PMID: 36150079 DOI: 10.1021/acs.jmedchem.2c01198
Abstract

The atypical Chemokine Receptor 3 (ACKR3), formerly known as CXC-chemokine receptor 7 (CXCR7), has been postulated to regulate platelet function and thrombus formation. Herein, we report the discovery and development of first-in-class ACKR3 agonists, which demonstrated superagonistic properties with Emax values of up to 160% compared to the endogenous reference ligand CXCL12 in a β-arrestin recruitment assay. Initial in silico screening using an ACKR3 homology model identified two hits, C10 (EC50 19.1 μM) and C11 (EC50 = 11.4 μM). Based on these hits, extensive structure-activity relationship studies were conducted by synthesis and testing of derivatives. It resulted in the identification of the novel thiadiazolopyrimidinone-based compounds 26 (LN5972, EC50 = 3.4 μM) and 27 (LN6023, EC50 = 3.5 μM). These compounds are selective for ACKR3 versus CXCR4 and show metabolic stability. In a platelet degranulation assay, these agonists effectively reduced P-selectin expression by up to 97%, suggesting potential candidates for the treatment of platelet-mediated thrombosis.

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