posted on 2020-05-20, 12:08authored byElnaz Menhaji-Klotz, Jessica Ward, Janice A. Brown, Paula M. Loria, Carina Tan, Kevin D. Hesp, Keith A. Riccardi, John Litchfield, Markus Boehm
The
atypical chemokine receptor CXCR7 has been studied in various
disease settings including immunological diseases and heart disease.
Efforts to elucidate the role of CXCR7 have been limited by the lack
of suitable chemical tools with a range of pharmacological profiles.
A high-throughput screen was conducted to discover novel chemical
matter with the potential to modulate CXCR7 receptor activity. This
led to the identification of a series of diphenylacetamides confirmed
in a CXCL12 competition assay indicating receptor binding. Further
evaluation of this series revealed a lack of activity in the functional
assay measuring β-arrestin recruitment. The most potent representative,
compound 10 (Ki = 597 nM),
was determined to be an antagonist in the β-arrestin assay (IC50 = 622 nM). To our knowledge, this is the first reported
small molecule β-arrestin antagonist for CXCR7, useful as an
in vitro chemical tool to elucidate the effects of CXCL12 displacement
with β-arrestin antagonism in models for diseases such as cardiac
injury and suitable as starting point for hit optimization directed
toward an in vivo tool compound for studying CXCR7 receptor pharmacology.