Abstract 4454: Identification of BAY-218, a potent and selective small-molecule AhR inhibitor, as a new modality to counteract tumor immunosuppression

Abstract

Re-constitution of anti-tumor T-cell responses by clinically-approved immune checkpoint inhibitors (ICIs) 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. In addition, 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 ligands such as 2,3,7,8-tetrachlorodibenzodioxine (TCDD). 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 in vitro 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 assessments. BAY-218 showed mono-therapeutic efficacy that was comparable to ICI treatment and further therapeutic improvement was achieved by combination with an anti-PD-L1 antibody. We were able to characterize 1,3-diaryl-pyrazin-6-one-5-carboxylic amides as a new and unprecedented class of AhR inhibitors as well as identify the key substitutions that contribute to the overall compound profile. Citation Format: Norbert Schmees, Ilona Gutcher, Ulrike Roehn, Horst Irlbacher, Detlef Stoeckigt, Benjamin Bader, Christina Kober, Lars Roese, Rafael Carretero, Iris Oezen, Ludiwg Zorn, Michael Platten, Ingo Volker Hartung, Bertolt Kreft, Hilmar Weinmann. Identification of BAY-218, a potent and selective small-molecule AhR inhibitor, as a new modality to counteract tumor immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4454.

Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas

“…Data were derived from ref. 33 . Statistical significance was determined by one-way ANOVA in combination with Tukey's honest significant difference test.…”

“…experimental HGG harbor a unique immunological vulnerability that could be therapeutically exploited by AHR inhibition. We therefore combined T cell-activating immunotherapy by immune checkpoint blockade (anti-PD-L1 antibody) with a small-molecule AHR inhibitor 33 to test the impact of the AHR-mediated dysregulated immune microenvironment found in IDH-mutant HGG (Fig. 7c,d).…”

“…Expression of TDO2 in TCGA low-grade glioma (LGG, n = 286) and HGG (n = 402) datasets. Data were derived from ref 33. .…”

Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives

“…Numerous AhR inhibitors have entered in vivo studies. Notably, BAY-218, a selective AhR blocker, increased therapeutic activity of anti-PD-L1 antibody in the CT26 colon carcinoma model (118,119).…”

Small molecule-based immunomodulators for cancer therapy

“…Compound 46 (BAY218): Schmees et al. 109 reported another small molecule 46 with potent inhibitory activity against AhR (IC 50 = 39.9 nmol/L). 46 could also enhanced the in vivo antitumor efficacy of anti-PD-L1 antibody in a CT-26 mouse model ( Fig.…”