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

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 Alan Wainwright; Gary E. Schiltz

doi:10.1021/acs.jmedchem.5c00026

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

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-GomezJacob M. Allen, Bakhtiar Yamini, Rimas V. Lukas, Derek Alan Wainwright^*, Gary E. Schiltz^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 vivo. In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC₅₀ 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.

Original language	English (US)
Pages (from-to)	4961-4987
Number of pages	27
Journal	Journal of Medicinal Chemistry
Volume	68
Issue number	4
DOIs	https://doi.org/10.1021/acs.jmedchem.5c00026
State	Published - Feb 27 2025

Funding

This work was supported in part by National Institutes of Health (NIH) Grants R01NS097851 (D.A.W. and G.E.S.), K02AG068617 (D.A.W.), R01NS129835 (D.A.W.), American Cancer Scholar Research Scholar Award RSG-21-058-01-CCE (D.A.W.), and the GBM Foundation (D.A.W.). This work was supported by the Northwestern University High Throughput Analysis Core, which received funding from the Lurie Cancer Center (NCI Grant CA060553) and the Acoustic liquid handler SIG (NIH S10OD023681). This work made use of the IMSERC NMR facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), the State of Illinois, the International Institute for Nanotechnology (IIN), and Northwestern University. Some of the work was completed in the Keck Biophysics Facility, a shared resource of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University supported in part by the NCI Cancer Center Support Grant P30CA060553. We thank Katherine A. Donovan, Eric S. Fischer, and the Fischer Lab Degradation Proteomics Initiative for collection of the global proteomics data supported by NIH CA214608 and CA218278. Global proteomics data will be publicly available at the Fischer Lab\u2019s Proteomics database: https://proteomics.fischerlab.org.

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Monsen, P. J., Bommi, P. V., Grigorescu, A. A., Lauing, K. L., Mao, Y., Berardi, P., Zhai, L., Ojo, O., Penco-Campillo, M., Koch, T., Egozi, M., Jha, S., Dunne, S. F., Jiang, H., Song, G., Zhang, F., Kregel, S., Vaziri-Gohar, A., Fanning, S. W., ... Schiltz, G. E. (2025). Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC). Journal of Medicinal Chemistry, 68(4), 4961-4987. https://doi.org/10.1021/acs.jmedchem.5c00026

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title = "Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)",

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 vivo. In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC50 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.",

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

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society.",

year = "2025",

month = feb,

day = "27",

doi = "10.1021/acs.jmedchem.5c00026",

language = "English (US)",

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Monsen, PJ, Bommi, PV, Grigorescu, AA, Lauing, KL, Mao, Y, Berardi, P, Zhai, L, Ojo, O, Penco-Campillo, M, Koch, T, Egozi, M, Jha, S, Dunne, SF, Jiang, H, Song, G, Zhang, F, Kregel, S, Vaziri-Gohar, A, Fanning, SW, Sanchez-Gomez, P, Allen, JM, Yamini, B, Lukas, RV, Wainwright, DA & Schiltz, GE 2025, 'Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)', Journal of Medicinal Chemistry, vol. 68, no. 4, pp. 4961-4987. https://doi.org/10.1021/acs.jmedchem.5c00026

TY - JOUR

T1 - Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)

AU - Monsen, Paige J.

AU - Bommi, Prashant V.

AU - Grigorescu, Arabela A.

AU - Lauing, Kristen L.

AU - Mao, Yingyu

AU - Berardi, Payton

AU - Zhai, Lijie

AU - Ojo, Oluwatomilayo

AU - Penco-Campillo, Manon

AU - Koch, Taylor

AU - Egozi, Michael

AU - Jha, Sonam

AU - Dunne, Sara F.

AU - Jiang, Hong

AU - Song, Guiqin

AU - Zhang, Fang

AU - Kregel, Steven

AU - Vaziri-Gohar, Ali

AU - Fanning, Sean W.

AU - Sanchez-Gomez, Pilar

AU - Allen, Jacob M.

AU - Yamini, Bakhtiar

AU - Lukas, Rimas V.

AU - Wainwright, Derek Alan

AU - Schiltz, Gary E.

PY - 2025/2/27

Y1 - 2025/2/27

N2 - 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 vivo. In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC50 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.

AB - 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 vivo. In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC50 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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SN - 0022-2623

VL - 68

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JF - Journal of Medicinal Chemistry

IS - 4

ER -

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

Abstract

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UN SDGs

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