Discovery of PF-07054894, a Potent Squaramide-Based CCR6 Antagonist Displaying High CXCR2 Selectivity

The
G protein-coupled receptor (GPCR) CCR6 mediates the migration
of pathogenic immune cells to the site of inflammation in response
to the chemokine CCL20. CCR6 is an attractive target for the treatment
of chronic autoimmune disease as antagonism of the receptor is expected
to block CCL20-mediated immune cell recruitment. High-throughput-screening
identified a squaramide-based, allosteric antagonist of CCR6 that
potently inhibited CCL20-mediated T cell chemotaxis, but it also inhibited
CXCL1-mediated neutrophil chemotaxis through CXCR2 antagonism. Lead
optimization achieved differentiation from CXCR2 through identification
of a methyl substituent-dependent selectivity switch or “magic
methyl for selectivity”. The mechanism for this effect is rooted
in different antagonist-induced ligand–receptor behaviors,
insurmountable for CCR6 and surmountable for CXCR2. Herein, we report
the discovery and preclinical evaluation of the CCR6 antagonist PF-07054894
(18l) which has advanced to clinical trials as a first
in class approach targeting the receptor.