Discovery of CCR8 Antagonist IDOR-1136-5177 for the Treatment of Cancer.

CCR8 is a GPCR mainly expressed in tumor-infiltrating T-regulatory cells (Treg) and high CCR8 expression is associated with poor prognosis in cancer. CCR8 and its ligand CCL1 may be involved in Treg recruitment, conversion and/or immunosuppressive function. Recently, pharmacological inhibition of CCR8 in mouse models has been reported to result in tumor regression and small molecule inhibitors of CCR8 have entered the clinic. Aiming to find a new class of CCR8 antagonists, a high throughput screen (HTS) of the Idorsia compound library was performed. HTS hits with a promising profile were identified and subsequent characterization revealed hERG as a key parameter that required further optimization. We reasoned that a strategy focused on discrete structural modifications would offer significant potential to reduce hERG inhibition. The lead optimization campaign we report led to the identification of compound 52 (IDOR-1136-5177), a highly potent CCR8 antagonist representing a new chemical class of CCR8 inhibitors with excellent in vitro and in vivo properties.