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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2025 Feb 13

PMID 39946350

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 Jha

Sara F Dunne

Hong Jiang

Guiqin Song

Fang Zhang

Steven Kregel

Ali Vaziri-Gohar

Sean W Fanning

Pilar Sanchez-Gomez

Jacob M Allen

Bakhtiar Yamini

Rimas V Lukas

Derek A Wainwright

Gary E Schiltz

Affiliations

Soon will be listed here.

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and nonenzymatic functions. Drugs targeting IDO1 enzyme activity have failed to improve the overall survival of patients with cancer. Developing new therapeutics that neutralize both enzyme- and nonenzyme-derived immunosuppressive IDO1 effects is therefore of high interest. We previously described a novel proteolysis targeting chimera (PROTAC), NU223612, that degrades IDO1 in cultured human glioblastoma (GBM) cells, as well as in well-established brain tumors, . In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC of 5 nM in human GBM cells. Mechanistic studies showed that IDO1 degradation occurred through the ubiquitin-proteasome system and was sustained for at least 2 days, supporting NU227326 as a highly potent IDO1 PROTAC suitable for further studies in GBM and other human cancers.

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