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Significant advances in targeting IDO1 (Indoleamine 2,3-dioxygenase 1) protein degradation are presented in a recent study by Monsen et al., through the development of novel PROTACs (Proteolysis Targeting Chimeras).

The researchers out of the Schiltz lab designed and synthesised a series of potent IDO1 PROTACs, with the lead compound NU227326 demonstrating exceptional potency with a 5 nM IDO1 DC50 in U87 cells.

The study employed comprehensive proteomics analysis to evaluate the selectivity of their lead compounds and identify potential off-target effects. Using a TimsTOF HT mass spectrometer coupled to a nanoElute LC system via a CaptiveSpray source, the team conducted detailed quantitative mass spectrometry analysis. The methodology involved sophisticated peptide separation using an Aurora Ultimate CSI 25×75 C18 UHPLC column, operated at 50°C with a 50-minute gradient.

This study is significant as it demonstrates effective targeting of both enzymatic and non-enzymatic functions of IDO1, potentially offering new therapeutic strategies for glioblastoma and other cancers.

The Aurora Series column’s high-resolution separation capabilities were crucial in enabling the detailed proteomic characterisation of the PROTAC’s selectivity profile.

Publication
Journal of Medicinal Chemistry

Authors

Paige J. Monsen, Prashant V. Bommi, Arabela A. Grigorescu, Kristen L. Lauing, Yingyu Mao, Payton Berardi, Lijie Zhai, Oluwatomilayo Ojo, Manon Penco-Campillo, Taylor Koch, Michael Egozi, Sonam V. Jha, Sara F. Dunne, Hong Jiang, Guiqin Song, Fang Zhang, Steven Kregel, Ali Vaziri-Gohar, Sean Fanning, Pilar Sanchez-Gomez, Jacob M. Allen, Bakhtiar Yamini, Rimas V. Lukas, Derek A. Wainwright, Gary E. Schiltz

Title

Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)