Abstract

Re-constitution of anti-tumor T cell responses by clinically approved immune checkpoint inhibitors (ICIs) represents a breakthrough cancer therapy. However, a substantial number of patients do not benefit from these new therapeutic modalities partly due to local immunosuppression in the tumor microenvironment. Oral small molecule inhibitors allow addressing for a new class of intracellular targets. This could result in a new generation of immunotherapeutic drugs that could improve the current standard of care.

The aryl hydrocarbon receptor (AhR) is seen as an attractive target in this regard and a screen for inhibitors on the compound library of about 3.2 million compounds delivered an unprecedented large list of confirmed structural classes as potential starting points. A comprehensive filtering process was applied focusing on application of stringent filter criteria to select diaryl-pyrazinone-carboxylic amides as the preferred lead series. A comprehensive SAR exploration was performed. Out of this optimization, BAY 2416964 was identified as the clinical candidate revealing the potential to stimulate various immune cell types. In a tumor efficacy model in vivo, BAY 2416964 showed mono-therapeutic efficacy that was comparable to an aPD-L1 antibody.

In this 45-minute presentation, Dr Norbert Schmees, Head of Life Science chemistry 2 at NUVISAN-ICB will take you through the discovery of AhR Antagonist BAY 2416964:

• SMOLs in IO
• The AhR as a target in IO
• From HTS to Lead Structure
• Lead Optimization and SAR
• Characterization of BAY 2416964

In a Q&A session following this case study presentation, it will be possible to discuss further on these or any other topics of interest.

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