4.7 Article

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

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 19, Pages 13365-13384

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01198

Keywords

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Funding

  1. Federal Ministry of Education and Research (BMBF)
  2. Baden-Wurttemberg Ministry of Science, Excellence Strategy of the German Federal and State Governments
  3. Luxembourg Institute of Health (LIH), Luxembourg National Research Fund (INTER/FNRS) [20/15084569]
  4. F.R.S.-FNRS-Televie [7.4593.19, 7.4529.19, 7.8504.20]
  5. Orion Research Foundation
  6. German Research Foundation (DFG) [374031971-TRR 240, 335549539-GRK2381]
  7. iFIT fellowship

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This study reports the discovery and development of first-in-class ACKR3 agonists, which demonstrated superagonistic properties in a fi-arrestin recruitment assay. Through structure-activity relationship studies, novel compounds with selective activity against ACKR3 were identified, showing potential as candidates for the treatment of platelet-mediated thrombosis.
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 fi-arrestin recruitment assay. Initial in silico screening using an ACKR3 homology model identified two hits, C10 (EC50 19.1 mu M) and C11 (EC50 = 11.4 mu M). 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 thiadiazolopyrimidinonebased compounds 26 (LN5972, EC50 = 3.4 mu M) and 27 (LN6023, EC50 = 3.5 mu M). 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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