CCR6 is a chemokine GPCR receptor that mediates the migration of inflammatory cells in response to its endogenous ligand CCL20. Antagonism of CCR6 would be expected to block immune cell recruitment and may offer a beneficial treatment option for patients suffering inflammatory bowel disease or psoriasis. A directed screening campaign identified novel negative allosteric modulators of the receptor. These hits enabled the first crystal structure of inactive CCR6 and the discovery of two novel binding sites. An important challenge for lead optimization was selectivity against the related chemokine receptor CXCR2, and how published clinical data for CXCR2 antagonists were used to define selectivity requirements will be discussed. Structure-based lead optimization in conjunction with an understanding of differential receptor binding kinetics led to the design of PF-07054894 as a potent, orally bioavailable CCR6 antagonist with high CXCR2 selectivity and efficacy in a pre-clinical model of skin inflammation. This talk will describe the hit to lead effort, SAR driving candidate selection, PK and efficacy in pre-clinical species, and pre-clinical in vitro safety pharmacology that led to the identification of a first-in-class clinical candidate targeting CCR6.

Discovery of the CCR6 antagonist PF-07054894 for the treatment of autoimmune disorders

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.