TY - JOUR
T1 - Discovery and Development of First-in-Class ACKR3/CXCR7 Superagonists for Platelet Degranulation Modulation
AU - Bayrak, Alp
AU - Mohr, Florian
AU - Kolb, Kyra
AU - Szpakowska, Martyna
AU - Shevchenko, Ekaterina
AU - Dicenta, Valerie
AU - Rohlfing, Anne Katrin
AU - Kudolo, Mark
AU - Pantsar, Tatu
AU - Günther, Marcel
AU - Kaczor, Agnieszka A.
AU - Poso, Antti
AU - Chevigné, Andy
AU - Pillaiyar, Thanigaimalai
AU - Gawaz, Meinrad
AU - Laufer, Stefan A.
N1 - Funding Information:
The TüCAD2 is a program funded by the Federal Ministry of Education and Research (BMBF) and the Baden-Württemberg Ministry of Science as part of the Excellence Strategy of the German Federal and State Governments. E.S. received support from the Excellence Initiative, by the means of an iFIT fellowship. A.C. and M.S. acknowledge funding by the Luxembourg Institute of Health (LIH), Luxembourg National Research Fund (INTER/FNRS grants 20/15084569), and F.R.S.-FNRS-Télévie (grants 7.4593.19, 7.4529.19, and 7.8504.20). T.P. acknowledges funding from Orion Research Foundation. K.K., V.D., and M.G. acknowledge funding from the German Research Foundation (DFG) (project number 374031971–TRR 240 for K.K. and M.G. and project number 335549539─GRK2381 for V.D. and M.G.). CSC-IT Center for Science Ltd. (Espoo, Finland) is acknowledged for computational resources. The authors thank Dr. Thales Kronenberger for editing a draft of this manuscript and Kristine Schmidt for language proofreading.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/10/13
Y1 - 2022/10/13
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85138892445
UR - https://pubmed.ncbi.nlm.nih.gov/36150079
U2 - 10.1021/acs.jmedchem.2c01198
DO - 10.1021/acs.jmedchem.2c01198
M3 - Article
C2 - 36150079
SN - 0022-2623
VL - 65
SP - 13365
EP - 13384
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -