Cell-Based Identification of New IDO1 Modulator Chemotypes

Hennes E, Lampe P, Dötsch L, Bruning N, Pulvermacher LM, Sievers S, Ziegler S, Waldmann H (2021) Angew Chem Int Ed Engl 

10. Februar 2021
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The immunoregulatory enzyme IDO1 strengthens cancer immune escape. The Waldmann lab and the Ziegler lab developed a new, robust fluorescence-based assay amenable to high throughput, which detects kynurenine in cells, a product of IDO1 activity. Screening of a 150,000-member compound library discovered unprecedented, potent IDO1modulators with different mechanisms of action, including direct IDO1 inhibitors, regulators of IDO1 expression and inhibitors of heme synthesis.

Three IDO1-modulator chemotypes were identified that bind to apo-IDO1 and compete with the heme cofactor. This new cell-based technology opens up novel opportunities for medicinal chemistry programs in immuno-oncology.

Validation of a coumarin-based sensor for detection of cellular kynurenine (1, Kyn) levels. (A) Cellular Kyn assay. Cells are treated with IFNγ, Trp and compounds. After 48 h, Kyn levels are detected using the Kyn sensor (2).

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