Combinatorial antitumor effects of indoleamine 2,3-dioxygenase inhibitor NLG919 and paclitaxel in a murine B16-F10 melanoma model

Meng, Xiangjing; Du, Guangying; Liang, Y. T.; Sun, Shanyue; Liu, Qiaofeng; Wang, Hongbo; Wang, Wenyan; Wu, Zimei; Tian, Jingwei

doi:10.1177/0394632017714696

Cited by 36 publications

(23 citation statements)

References 16 publications

(28 reference statements)

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“…These samples were stored at -80˚C for tests. Plasma IFN-γ level was determined by using mice ELISA kit according to the manufacturer's instructions [21].…”

Section: Measurements For Plasma Ifn-γ Level In Melanoma-bearing Micementioning

confidence: 99%

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

et al. 2020

PLoS ONE

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The increased PD-L1 expression induces poorer prognosis in melanoma. The small molecule inhibitors of PD-1/PD-L1 pathways have been an encouraging drug development strategy because of good affinity and oral bioavailability without immunogenicity and immunotoxicities of PD-1/PD-L1 antibodies. In this study, we studied the effects of PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, on PD-1/PD-L1 binding and the cytokines secretion in human CD3 + cells in vitro. We also investigated the antitumor and immunomodulatory activity of PCC0208025 and the pharmacokinetics properties in B16-F10 melanoma-bearing mice. The results showed that PCC0208025 inhibited the PD-1/PD-L1 proteins binding, and rescued PD-L1-mediated inhibition of IFN-γ production in human CD3 + T cells in vitro. Furthermore, in B16-F10 melanoma-bearing mice, PCC0208025 presented the antitumor effects, enhanced IFN-γ levels in plasma, increased the frequency of CD3 + CD8 + T and CD8 + IFN-γ + T and the ratios of CD8 + /Treg, and deceased the CD4 + CD25 + CD127 low/− (Treg) number in tumor. Pharmacokinetics study found that PCC0208025 was absorbed and distributed into the tumors with much higher concentrations than those of the blockade against PD-1/PD-L1 binding. Our work suggests that PCC0208025 exhibited anti-tumor effects through inhibiting Treg expansion and increasing cytotoxic activity of tumor-infiltrating CD8 + T cells by the blockade of PD-1/PD-L1 binding, which may provide the pharmacological basis to develop small molecule inhibitors of PD-1/PD-L1 binding for PCC0208025 as a lead compound.

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“…These samples were stored at -80˚C for tests. Plasma IFN-γ level was determined by using mice ELISA kit according to the manufacturer's instructions [21].…”

Section: Measurements For Plasma Ifn-γ Level In Melanoma-bearing Micementioning

confidence: 99%

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

et al. 2020

PLoS ONE

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“…Tumors expressing IDO1 have a more aggressive phenotype and lead to poorer prognosis than tumors that do not express this protein (Godin-Ethier et al 2011). There are several ongoing studies investigating the effect of the IDO inhibitor indoximod both alone and in combination with other antitumoral agents (Assal et al 2015, Jiang et al 2017, Meng et al 2017, Tomek et al 2017.…”

Section: Lag-3 Also Called Cd223 Lag-3 Is Expressed On Activated T Cmentioning

confidence: 99%

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

Cunha

Marcello

Rocha-Santos

et al. 2017

Endocrine-Related Cancer

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Immune checkpoint inhibitors are agents that act by inhibiting the mechanisms of immune escape displayed by various cancers. The success of immune checkpoint inhibitors against several tumors has promoted a new treatment strategy in clinical oncology, and this has encouraged physicians to increase the number of patients who receive the immune checkpoint therapy. In the present article, we review the main concepts regarding immune checkpoint mechanisms and how cancer disrupts them to undergo immune escape. In addition, we describe the most essential concepts related to immune checkpoint inhibitors. We critically review the literature on preclinical and clinical studies of the immune checkpoint inhibitors as a treatment option for thyroid cancer, ovarian carcinoma, pancreatic adenocarcinoma, adrenocortical carcinoma and neuroendocrine tumors. We present the challenges and the opportunities of using immune checkpoint inhibitors against these endocrine malignancies, highlighting the breakthroughs and pitfalls that have recently emerged.

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“…To the best of our knowledge, only several IDO1 inhibitors have entered clinical trials, such as INCB024360 (Epacadostat) 13–15 , the imidazole NLG919 16 , 17 and NLG-8189 (Indoximod, 1-Methyl-tryptophan (1-MT); Supplementary Figure S1 ). The most widely studied of these was 1-MT.…”

Section: Introductionmentioning

confidence: 99%

A highly potent and selective inhibitor Roxyl-WL targeting IDO1 promotes immune response against melanoma

Wang

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Indoleamine 2,3-dioxygenase 1 (IDO1) activity links to immune escape of cancers. Inhibition of IDO1 provides a new approach for cancer treatment. Most clinical IDO1 drugs show marginal efficacy as single agents. On basis of molecular docking and pharmacophore modelling, a novel inhibitor Roxyl-WL was discovered with a half maximal inhibitory concentration (IC50) value of 1 nM against IDO1 and 10–100-fold increased potent activity compared with IDO1 drugs in clinical trials. Roxyl-WL displayed excellent kinase spectrum selectivity with no activity out of the 337 protein kinases. In vitro, Roxyl-WL effectively augmented the proliferation of T cells and reduced the number of regulatory T cell (Tregs).When administered to melanoma (B16F10) tumor-bearing mice orally, Roxyl-WL significantly suppressed tumor growth and induced immune response.

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Combinatorial antitumor effects of indoleamine 2,3-dioxygenase inhibitor NLG919 and paclitaxel in a murine B16-F10 melanoma model

Cited by 36 publications

References 16 publications

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

A highly potent and selective inhibitor Roxyl-WL targeting IDO1 promotes immune response against melanoma

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