BAY-218: A Breakthrough in Targeting Tumor Immunosuppression through AhR Inhibition

Clinically approved immune checkpoint inhibitors have revolutionized cancer treatment by re-activating anti-tumor T-cells, but many patients remain unaffected due to the tumor microenvironment's immunosuppressive nature. The limited dosing flexibility of these inhibitors also poses challenges in managing side effects. The development of oral small molecule inhibitors presents a promising alternative, offering the potential to target intracellular pathways for a controlled duration, thus optimizing efficacy and safety in both standalone and combined treatments with existing therapies.

Many tumors overexpress enzymes like IDO1 and TDO2, leading to the conversion of tryptophan into immunosuppressive kynurenine. This process is mediated through the activation of the aryl hydrocarbon receptor (AhR). Inhibiting AhR could potentially restore T-cell function and promote tumor rejection. However, finding specific AhR inhibitors has been considered difficult due to the receptor's preference for polyaromatic ligands, such as TCDD.

A high-throughput screening of 4 million compounds was conducted, resulting in a diverse set of leads after applying strict lead-likeness criteria. Among the drug-like compounds identified, 1,3-diaryl-pyrazin-6-one-5-carboxylic amides emerged as a prime lead series. Extensive structure-activity relationship studies and in vitro validations were carried out, with a focus on enhancing lipophilicity efficiency to achieve a balance between potency and favorable pharmacokinetics and CYP450 interactions.

Several promising candidates were selected for in vivo evaluation, with BAY-218 demonstrating significant therapeutic effects comparable to those of immune checkpoint inhibitors. The combination of BAY-218 with an anti-PD-L1 antibody showed enhanced therapeutic benefits. This research has successfully identified 1,3-diaryl-pyrazin-6-one-5-carboxylic amides as a novel class of AhR inhibitors and determined the key structural features that contribute to their therapeutic profile.

The study was presented by Norbert Schmees and colleagues at the American Association for Cancer Research Annual Meeting in 2019, highlighting BAY-218 as a potent and selective AhR inhibitor, offering a new approach to overcoming tumor-induced immunosuppression.