An IDO pathway inhibitor
NLG919 is a novel and orally-bioavailable small-molecule inhibitor of indoleamine 2,3-dioxygenase (IDO) pathway, a crucial pathway involved in allergic inflammation that mediates immunosuppressive effects through metabolization of tryptophan (Trp) to kynurenine and affects differentiation and proliferation of T cells through inducing downstream signaling via GCN2, mTOR and AHR, with values of inhibition constant Ki and half maximal effective concentration EC50 of 7 nM and 75 nM respectively. Due to the established correlation of IDO pathway with various malignancies, the IDO pathway inhibition as well as its desirable pharmacological and biological properties potentiates NLG919 to be used for the treatment of immunosuppression associated with cancer.
Reference
Mario R. Mautino, Firoz A. Jaipuri, Jesse Waldo, Sanjeev Kumar, James Adams, Clarissa Van Allen, Agnieszka Marcinowicz-Flick, David Munn, Nicholas Vahanian, Charles J. Link. NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 491. doi:10.1158/1538-7445.AM2013-491
| Cell experiment [1]: | |
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Cell lines |
Human and mouse IDO+ pDCs |
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Preparation method |
Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
37oC |
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Applications |
NLG919 potently blockes IDO-induced T cell suppression and restores robust T cell responses with an EC50=90 nM. NLG919 also abrogates IDO-induced suppression of antigen-specific T cells (OT-I or pmel-1) in vitro, (ED50=130 nM ) using mouse IDO+ pDCs from tumor-draining lymph nodes. |
| Animal experiment [1]: | |
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Animal models |
Mice bearing large established B16F10 tumor |
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Dosage form |
NLG919 was dosed either dissolved in the water at 3 mg/mL, plus a daily dose of 6 mg injected via IP, or administered subcutaneously at 1 mg/dose twice a day via injection plus 360 μg/day via an SC osmotic pump. |
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Applications |
NLG919 markedly enhances the antitumor responses of naive, resting pmel-1 cells to vaccination with cognate hgp100 peptide plus CpG-1826 in IFA. NLG919 plus pmel-1/vaccine produces a dramatic collapse of tumor size within 4 days of vaccination (~95% reduction in tumor volume compared to control animals receiving pmel-1/vaccine alone without NLG919). |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: 1. Mario R. Mautino, Firoz A et al. NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 491. | |
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