Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma

Bollu, Lakshmi Reddy; Bommi, Prashant V.; Monsen, Paige J; Zhai, Lijie; Lauing, Kristen L.; Bell, April; Kim, Miri; Ladomersky, Erik; Yang, Xinyu; Platanias, Leonidas C.; Matei, Daniela; Munshi, Hidayatullah G.; Hashizume, Rintaro; Wu, Jennifer D.; Zhang, Bin; James, C. David; Chen, Peiwen; Kocherginsky, Masha; Horbinski, Craig; Cameron, Michael D.; Grigorescu, Arabela A.; Yamini, Bakhtiar; Lukas, Rimas V.; Schiltz, Gary E.; Wainwright, Derek A.

doi:10.1021/acs.jmedchem.2c00771

Cited by 19 publications

(11 citation statements)

References 55 publications

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“…( 34 ). Thereafter, an additional IDO1-based PROTAC was reported to be therapeutically active in a mouse model of glioblastoma ( 35 ). Alternative IDO1-based therapies are expected to emerge by selectively targeting the non-enzymatic function of IDO1 in tumor cells once the signaling pathway mediated by IDO1 is fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells

Rossini,

Ambrosino,

Volpi

et al. 2024

Front. Immunol.

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The tryptophan-degrading enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a plastic immune checkpoint molecule that potently orchestrates immune responses within the tumor microenvironment (TME). As a heme-containing protein, IDO1 catalyzes the conversion of the essential amino acid tryptophan into immunoactive metabolites, called kynurenines. By depleting tryptophan and enriching the TME with kynurenines, IDO1 catalytic activity shapes an immunosuppressive TME. Accordingly, the inducible or constitutive IDO1 expression in cancer correlates with a negative prognosis for patients, representing one of the critical tumor-escape mechanisms. However, clinically trialed IDO1 catalytic inhibitors disappointed the expected anti-tumor efficacy. Interestingly, the non-enzymatic apo-form of IDO1 is still active as a transducing protein, capable of promoting an immunoregulatory phenotype in dendritic cells (DCs) as well as a pro-tumorigenic behavior in murine melanoma. Moreover, the IDO1 catalytic inhibitor epacadostat can induce a tolerogenic phenotype in plasmacytoid DCs, overcoming the catalytic inhibition of IDO1. Based on this recent evidence, IDO1 plasticity was investigated in the human ovarian cancer cell line, SKOV-3, that constitutively expresses IDO1 in a dynamic balance between the holo- and apo-protein, and thus potentially endowed with a dual function (i.e., enzymatic and non-enzymatic). Besides inhibiting the catalytic activity, epacadostat persistently stabilizes the apo-form of IDO1 protein, favoring its tyrosine-phosphorylation and promoting its association with the phosphatase SHP-2. In SKOV-3 cells, both these early molecular events activate a signaling pathway transduced by IDO1 apo-protein, which is independent of its catalytic activity and contributes to the tumorigenic phenotype of SKOV-3 cells. Overall, our findings unveiled a new mechanism of action of epacadostat on IDO1 target, repositioning the catalytic inhibitor as a stabilizer of the apo-form of IDO1, still capable of transducing a pro-tumorigenic pathway in SKOV-3 tumor. This mechanism could contribute to clarify the lack of effectiveness of epacadostat in clinical trials and shed light on innovative immunotherapeutic strategies to tackle IDO1 target.

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Section: Discussionmentioning

confidence: 99%

Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells

Rossini,

Ambrosino,

Volpi

et al. 2024

Front. Immunol.

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“…Recently, a proteolysis targeting chimera (PROTAC) has been developed and studied in a preclinical model of glioblastoma, showing a therapeutic potential. 50 …”

Section: Discussionmentioning

confidence: 99%

The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma

et al. 2023

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Indoleamine 2,3 dioxygenase 1 (IDO1), a leader tryptophan-degrading enzyme, represents a recognized immune checkpoint molecule. In neoplasia, IDO1 is often highly expressed in dendritic cells infiltrating the tumor and/or in tumor cells themselves, particularly in human melanoma. In dendritic cells, IDO1 does not merely metabolize tryptophan into kynurenine but, after phosphorylation of critical tyrosine residues in the non-catalytic small domain, it triggers a signaling pathway prolonging its immunoregulatory effects by a feed-forward mechanism. We here investigated whether the non-enzymatic function of IDO1 could also play a role in tumor cells by using B16-F10 mouse melanoma cells transfected with either the wild-type Ido1 gene ( Ido1 WT ) or a mutated variant lacking the catalytic, but not signaling activity ( Ido1 H350A ). As compared to the Ido1 WT -transfected counterpart (B16 WT ), B16-F10 cells expressing Ido1 H350A (B16 H350A ) were characterized by an in vitro accelerated growth mediated by increased Ras and Erk activities. Faster growth and malignant progression of B16 H350A cells, also detectable in vivo , were found to be accompanied by a reduction in tumor-infiltrating CD8 + T cells and an increase in Foxp3 + regulatory T cells. Our data, therefore, suggest that the IDO1 signaling function can also occur in tumor cells and that alternative therapeutic approach strategies should be undertaken to effectively tackle this important immune checkpoint molecule.

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“…In addition, unlike traditional occupancy-based inhibition, PROTACs may act catalytically. 20 There are a few reports already proving that TPD does not require drug saturation, 55 as it can exert degradation function through a catalytic mechanism at lower concentrations, and its efficacy can accumulate over time.…”

Section: Degradation Of α-Syn Aggregates and Total Tau Was Induced By...mentioning

confidence: 99%

Discovery of Effective Dual PROTAC Degraders for Neurodegenerative Disease-Associated Aggregates

Zhu,

Zhang,

Chen

et al. 2024

J. Med. Chem.

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The aggregation of specific proteins is a histopathological hallmark in various neurodegenerative diseases (NDs), among which Alpha-synuclein (α-Syn) and tau have received increased attention. The targeted protein degradation (TPD) strategy has been studied in the treatment of NDs, but multitarget bifunctional molecules have been ignored. Herein, a series of effective dual PROTAC degraders were developed, which could degrade α-Syn aggregates and total tau simultaneously. The degradation effects were evaluated in vitro, and the results showed that T3 could significantly knockdown α-Syn aggregates and total tau in the degradation efficiency with DC 50 of 1.57 ± 0.55 and 4.09 ± 0.90 μM, respectively. Further mechanistic exploration showed that the degradation effect was mediated by the ubiquitin− proteasome system (UPS). Additionally, the therapeutic efficacy of T3 was confirmed in an MPTP-induced PD mouse model. Our results suggest that these dual PROTACs may provide a potential therapeutic strategy for NDs.

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Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma

Cited by 19 publications

References 55 publications

Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells

Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells

The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma

Discovery of Effective Dual PROTAC Degraders for Neurodegenerative Disease-Associated Aggregates

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