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

Alp Bayrak, Florian Mohr, Kyra Kolb, Martyna Szpakowska, Ekaterina Shevchenko, Valerie Dicenta, Anne Katrin Rohlfing, Mark Kudolo, Tatu Pantsar, Marcel Günther, Agnieszka A. Kaczor, Antti Poso, Andy Chevigné, Thanigaimalai Pillaiyar*, Meinrad Gawaz*, Stefan A. Laufer*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)13365-13384
Number of pages20
JournalJournal of Medicinal Chemistry
Volume65
Issue number19
Early online date23 Sep 2022
DOIs
Publication statusPublished - 13 Oct 2022

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