Discovery of Imidazopyridines as Potent Inhibitors of Indoleamine 2,3-Dioxygenase 1 for Cancer Immunotherapy

Zhang, Liping; Cherney, Emily C.; Zhu, Xiaohan; Lin, Tai-an; Gullo-Brown, Johnni; Maley, Derrick; Johnston-Allegretto, Kathy; Kopcho, Lisa M.; Fereshteh, Mark; Huang, Christine; Li, Xin; Traeger, Sarah C.; Dhar, Gopal; Anandam, Aravind; Mahankali, Sandeep; Padmanabhan, Shweta; Rajanna, Prabhakar; Murali, Venkata; Mariappan, T. Thanga; Borzilleri, R. M.; Vite, Gregory D.; Hunt, John T.; Balog, Aaron

doi:10.1021/acsmedchemlett.1c00014

Cited by 9 publications

(4 citation statements)

References 24 publications

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“…Type I, II, and III inhibitors bind to the holoenzyme encompassing the substrate pocket (pocket A) and pockets B and C above the heme. Type IV inhibitors bind to the apoenzyme devoid of the heme prosthetic group, still occupying pocket A and filling pocket D exposed by the absence of the heme. ,, For example, linrodostat 6 (BMS-986205) and similar compounds (Figure ) have been suggested by either crystal structure, docking, or modeling to bind to the IDO1 apoenzyme and have been classified as type IV inhibitors. ,,,− These inhibitors all contain a para -haloaryl moiety that binds in pocket A, make a crucial hydrogen bond with Ser-167, and have a middle core that spans the space of the absent heme with an attachment to a lipophilic aryl group that binds in pocket D. Linrodostat and the close analogs 7 (reversed amide of linrodostat) and 8 (benzimidazole isostere of linrodostat) were based on a cyclohexyl core with a direct attachment to the fluoroquinoline. Linrodostat 6 is apparently still in clinical trials and the phase 1/2A trial of 7 (BMS-986242) was terminated .…”

Section: Introductionmentioning

confidence: 99%

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme

et al. 2021

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Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed a class of inhibitors with a conformationally constrained bicyclo[3.1.0]hexane core. These potently inhibited IDO1 in a cellular context by binding to the apoenzyme, as elucidated by biochemical characterization and X-ray crystallography. A SKOV3 tumor model was instrumental in differentiating compounds, leading to the identification of IACS-9779 (62) and IACS-70465 (71). IACS-70465 has excellent cellular potency, a robust pharmacodynamic response, and in a human whole blood assay was more potent than linrodostat (BMS-986205). IACS-9779 with a predicted human efficacious once daily dose below 1 mg/kg to sustain >90% inhibition of IDO1 displayed an acceptable safety margin in rodent toxicology and dog cardiovascular studies to support advancement into preclinical safety evaluation for human development.

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Section: Introductionmentioning

confidence: 99%

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme

et al. 2021

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“…In addition to the above inhibitors, structural elucidation studies have also led to the discovery of imidazopyridines as potent IDO1 inhibitors ( 132 ) and substituted oxalamides as novel heme-displacing IDO1 inhibitors ( 133 ), as well as the development of first in class IACS-9779 and IACS-70465 inhibitors that bind the IDO1 apoenzyme ( 134 ). Anti-cancer efficacy of the mentioned above agents has been demonstrated in preclinical models; however, they have not been explored yet in clinical trials.…”

Section: Targeting the Kynurenine Pathway For Anti-cancer Treatmentmentioning

confidence: 99%

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

León-Letelier,

Dou,

Vykoukal

et al. 2023

Front. Oncol.

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The kynurenine pathway (KP) and associated catabolites play key roles in promoting tumor progression and modulating the host anti-tumor immune response. To date, considerable focus has been on the role of indoleamine 2,3-dioxygenase 1 (IDO1) and its catabolite, kynurenine (Kyn). However, increasing evidence has demonstrated that downstream KP enzymes and their associated metabolite products can also elicit tumor-microenvironment immune suppression. These advancements in our understanding of the tumor promotive role of the KP have led to the conception of novel therapeutic strategies to target the KP pathway for anti-cancer effects and reversal of immune escape. This review aims to 1) highlight the known biological functions of key enzymes in the KP, and 2) provide a comprehensive overview of existing and emerging therapies aimed at targeting discrete enzymes in the KP for anti-cancer treatment.

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“…The KP has recently been identified as a promising target to increase healthy longevity in age-related diseases. Therapies targeting the KP so far have focused on cancer-related therapeutics through the use of IDO inhibitors, which weaken the immunosuppressive functions by suppressing the KP, www.co-hivandaids.com starving the cell of energy [63,65,66]. Therapeutic targets from a senotherapy perspective takes the opposite approach, increasing energy production.…”

Section: The Kynurenine Pathway As a Senotherapeutic Targetmentioning

confidence: 99%

HIV and comorbidities – the importance of gut inflammation and the kynurenine pathway

MacCann

Landay

Mallon

2022

Current Opinion in HIV and AIDS

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Purpose of reviewThe purpose of this article is to review alterations in microbiota composition, diversity, and functional features in the context of chronic inflammation and comorbidities associated with HIV infection. Recent findingsThe gut microbiome is an important mediator of host immunity, and disruption of gut homeostasis can contribute to both systemic inflammation and immune activation. Ageing and HIV share features of intestinal damage, microbial translocation and alterations in bacterial composition that contribute to a proinflammatory state and development of age-related comorbidities. One such inflammatory pathway reviewed is the nicotinamide adenine dinucleotide (NADþ) producing kynurenine pathway (KP). Kynurenine metabolites regulate many biological processes including host-microbiome communication, immunity and oxidative stress and the KP in turn is influenced by the microbiome environment. Ageassociated decline in NADþ is implicated as a driving factor in many age-associated diseases, including those seen in people with HIV (PWH). Recent studies have shown that KP can influence metabolic changes in PWH, including increased abdominal adiposity and cardiovascular disease. Furthermore, KP activity increases with age in the general population, but it is elevated in PWH at all ages compared to agematched controls. Host or microbiome-mediated targeting of this pathway has merits to increase healthy longevity and has potential therapeutic applications in PWH. SummaryAs a growing proportion of PWH age, many face increased risks of developing age-related comorbidities. Chronic inflammation, a pillar of geroscience, the science of ageing and of age-related disease, is influenced by the gut microbiome and its metabolites. Combined, these contribute to a systemic inflammatory signature. Advances in geroscience-based approaches and therapeutics offer a novel paradigm for addressing age-related diseases and chronic inflammation in HIV infection. Whether targeted inhibition of KP activity alleviates pathological conditions or promotes successful ageing in PWH remains to be determined.

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Discovery of Imidazopyridines as Potent Inhibitors of Indoleamine 2,3-Dioxygenase 1 for Cancer Immunotherapy

Cited by 9 publications

References 24 publications

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

HIV and comorbidities – the importance of gut inflammation and the kynurenine pathway

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