Re-constitution of anti-tumor T-cell responses by clinically-approved immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 represents a breakthrough cancer therapy. Nevertheless, a substantial number of patients do not benefit from these new therapeutic modalities chiefly due to local immunosuppression in the tumor microenvironment. The long circulation time of ICIs restricts options to modify dosing regimens for management of adverse effects. Oral small molecule inhibitors as next generation immune-oncology agents may – in contrast to antibodies – allow targeting of intracellular targets for a defined duration of time. This will permit a fine-tuning of efficacy versus tolerability in single-agent treatment as well as in combination with approved ICIs.The overexpression of indole dioxygenase (IDO1) and tryptophan dioxygenase (TDO2) by many tumors results in increased metabolism of tryptophan (TRP) into kynurenine (KYN), which induces immunosuppression via activation of the aryl hydrocarbon receptor (AHR). Inhibition of AHR was proposed to restore T-cell function and induce tumor rejection. However, it was expected that identification of selective lead candidates for AHR inhibition would be challenging due to the known affinity of the AHR ligand binding site for polyaromatic, non-drug-like ligands. A library of 4 million compounds was screened in a cell based HTS campaign. A thorough hit reduction process was performed based on stringent filter parameters for lead-likeness. This process delivered a hit set of significant chemical diversity. Out of several compound classes with drug-like properties, 1,3-diaryl-pyrazin-6-one-5-carboxylic amides were selected as a preferred lead series. A comprehensive SAR exploration, including mechanistic and functional validation, was performed. Lead optimization was strongly emphasized on improving lipophilicity efficiency (LLE) to balance potency with a viable PK and CYP450 interaction profile. Several candidates suitable for in vivo profiling were identified and BAY-218 was advanced to in depth pharmacodynamic and pharmacokinetic in vivo assessment. BAY-218 showed in vivo mono-therapeutic efficacy that was comparable to ICI treatment and further therapeutic improvement was achieved by combination with an aPD-L1 antibody. We characterized 1,3-diaryl-pyrazin-6-one-5-carboxylic amides as an unprecedented class of AHR inhibitors and identified the key substitutions that contribute to the overall compound profile.

Identification of BAY-218: A potent and selective small molecule AHR inhibitor, as a new modality to counteract tumor immunosuppression

2019 Spring National Meeting

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