Recent advances in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

Wang, Xiuxiu; Sun, Siyu; Dong, Qingqing; Wu, Xiao-xiang; Tang, Wei; Xing, Ya-Qun

doi:10.1039/c9md00208a

Cited by 25 publications

(16 citation statements)

References 106 publications

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“…18 Although various compounds of tryptophan or indole analogues were studied as IDO1 inhibitors, the carbazole class has not reported any inhibitory activity against IDO1 yet. 23,39 The computational docking data between compounds 1-3 and apo-IDO1 enzyme (PDB id: 6AZV) were in good accordance with the results of IDO1 inhibition assay. Docking analysis proposed that compounds 1-3 interact with both the A-pocket and abandoned heme pocket of the IDO1 apoenzyme by hydrogen bonds and hydrophobic interactions.…”

Section: Resultssupporting

confidence: 64%

Jejucarbazoles A–C, carbazole glycosides with indoleamine 2,3-dioxygenase 1 inhibitory activity fromStreptomycessp. KCB15JA151

et al. 2021

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Section: Resultssupporting

confidence: 64%

Jejucarbazoles A–C, carbazole glycosides with indoleamine 2,3-dioxygenase 1 inhibitory activity fromStreptomycessp. KCB15JA151

et al. 2021

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“…It recently underwent the phase I/II clinical trials and is currently during phase III trials in combination with checkpoint blockade. However, the latest results from one of the phase III clinical studies indicate that it does not improve the effectiveness of pembrolizumab in patients with unresectable or metastatic melanoma [ 74 , 155 , 156 , 157 ].…”

Section: Modulation Of Kynurenine Pathway Activity In the Management Of Neoplastic Diseasesmentioning

confidence: 99%

“…[ 43 , 44 , 45 , 46 , 47 , 181 ]. Additionally, recent preclinical evidence indicates that the IDO1 inhibitors synergize the effects of tumor immuno- and chemotherapies and help to solve the problem of tumor resistance against them [ 83 , 93 , 105 , 106 , 107 , 108 , 112 , 113 , 119 , 120 , 129 , 132 , 133 , 136 , 137 , 143 , 146 , 151 , 154 , 155 , 156 , 157 , 171 ]. In turn, the discoveries concerning the role of IDO1 in tumor angiogenesis suggest that inhibiting its activity may effectively suppress this process, providing a potentially effective solution in the prevention of tumor development and metastasis.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Kynurenines as a Novel Target for the Treatment of Malignancies

2021

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Malignancies are unquestionably a significant public health problem. Their effective treatment is still a big challenge for modern medicine. Tumors have developed a wide range of mechanisms to evade an immune and therapeutic response. As a result, there is an unmet clinical need for research on solutions aimed at overcoming this problem. An accumulation of tryptophan metabolites belonging to the kynurenine pathway can enhance neoplastic progression because it causes the suppression of immune system response against cancer cells. They are also involved in the development of the mechanisms responsible for the resistance to antitumor therapy. Kynurenine belongs to the most potent immunosuppressive metabolites of this pathway and has a significant impact on the development of malignancies. This fact prompted researchers to assess whether targeting the enzymes responsible for its synthesis could be an effective therapeutic strategy for various cancers. To date, numerous studies, both preclinical and clinical, have been conducted on this topic, especially regarding the inhibition of indoleamine 2,3-dioxygenase activity and their results can be considered noteworthy. This review gathers and systematizes the knowledge about the role of the kynurenine pathway in neoplastic progression and the findings regarding the usefulness of modulating its activity in anticancer therapy.

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“…Since IDO1 plays an important role in cancer immunotherapy and neurological diseases, searching for highly active inhibitors is now a focus of research and development efforts by pharmaceutical companies and academic research institutions [8–30] . Various molecular scaffolds with inhibitory activity against IDO1 have been documented in the academic and patent literature [8–30] . To date, several IDO1 inhibitors such as Epacadostat, PF‐06840003, NLG‐919 and BMS‐986205 have advanced to clinical trials (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

A Series of 2‐((1‐Phenyl‐1H‐imidazol‐5‐yl)methyl)‐1H‐indoles as Indoleamine 2,3‐Dioxygenase 1 (IDO1) Inhibitors

et al. 2021

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Dedicated to the memory of Prof. Walter A. SzarekIndoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC 50 = 0.16 μM, EC 50 = 0.3 μM). Structuralactivity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.

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Recent advances in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

Abstract: This review summarizes the recent development of IDO1 inhibitors, focusing on structures, enzymatic inhibitory activity, selectivity and other biological activities.

Cited by 25 publications

References 106 publications

Jejucarbazoles A–C, carbazole glycosides with indoleamine 2,3-dioxygenase 1 inhibitory activity fromStreptomycessp. KCB15JA151

Jejucarbazoles A–C, carbazole glycosides with indoleamine 2,3-dioxygenase 1 inhibitory activity fromStreptomycessp. KCB15JA151

Kynurenines as a Novel Target for the Treatment of Malignancies

A Series of 2‐((1‐Phenyl‐1H‐imidazol‐5‐yl)methyl)‐1H‐indoles as Indoleamine 2,3‐Dioxygenase 1 (IDO1) Inhibitors

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