1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemENavoximodCat. No.: HY-18770BCAS No.: 1402837-78-8Synonyms: GDC-0919; NLG-919分式: CHFNO分量: 316.37作靶點(diǎn): Indoleamine 2,3-Dioxygenase (IDO)作通路: Metabolic Enzyme/Protease儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1

2、month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 100 mg/mL (316.09 mM; Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 3.1609 mL 15.8043 mL 31.6086 mL5 mM 0.6322 mL 3.1609 mL 6.3217 mL10 mM 0.3161 mL 1.5804 mL 3.1609 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。體內(nèi)實(shí)驗(yàn)請根據(jù)您的實(shí)驗(yàn)動物和給藥式選擇適當(dāng)?shù)娜芙獍?，配制前請先配制澄清的儲備液，再依次添?/p>

3、助溶劑(為保證實(shí)驗(yàn)結(jié)果的可靠性，體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使；澄清的儲備液可以根據(jù)儲存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 3 mg/mL (9.48 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 3 mg/mL (9.48 mM); Clear solution3. 請依序添加每種溶劑： 10% DMSO

4、90% corn oil1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 3 mg/mL (9.48 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Navoximod (GDC-0919; NLG-919)種有效的 IDO (indoleamine-(2,3)-dioxygenase) 抑制劑，Ki/EC50 分別為 7 nM/75 nM。IC50 & Target IDO IDO7 nM (Ki) 75 nM (EC50)體外研究 Using IDO-expressing human

5、 monocyte-derived dendritic cells (DCs) in allogeneic mixed lymphocytereaction (MLR) reactions, Navoximod (NLG919) potently blocks IDO-induced T cell suppression and restoresrobust T cell responses with an ED50=80 nM. Similarly, using IDO-expressing mouse DCs from tumor-draining lymph nodes, Navoxim

6、od abrogates IDO-induced suppression of antigen-specific T cells (OT-I) invitro, with ED50=120 nM 1. Navoximod inhibits the IDO activity in a concentration-dependent manner withan EC50 of 0.95M. PEG2k-Fmoc-NLG(L) is less active (EC50 of 3.4M) in inhibiting IDO compared withfree Navoximod while PEG2k

7、-Fmoc-NLG(S) is least active (EC5010M). Coculture of IDO+tumor cells withsplenocytes isolated from BALB/c mice leads to significant inhibition of T-cell proliferation. This inhibition issignificantly attenuated when the mixed cells are treated with Navoximod. PEG2k-Fmoc-NLG(L) is alsoactive in rever

8、sing the inhibitory effect of tumour cells although slightly less potent than Navoximod 3.體內(nèi)研究 VNavoximod (NLG919) is orally bioavailable (F70%); and has a favorable pharmacokinetic and toxicityprofile. In mice, a single oral administration of Navoximod reduces the concentration of plasma and tissue

9、Kyn by 50%. In vivo, in mice bearing large established B16F10 tumors, administration of Navoximodmarkedly enhances the anti-tumor responses of nave, resting pmel-1 cells to vaccination with cognatehgp100 peptide plus CpG-1826 in IFA. In this stringent established-tumor model, Navoximod plus pmel-1/v

10、accine produce a dramatic collapse of tumor size within 4 days of vaccination (95% reduction in tumorvolume compare to control animals receiving pmel-1/vaccine alone without Navoximod) 1. When combinedwith Temozolomide (TMZ)+radiation therapy (RT), both Navoximod and 1-methyl-D-tryptophan (D-1MT,ind

11、oximod) enhance survival relative to mice treated with TMZ+RT alone 2.PROTOCOLCell Assay 3 The IDO inhibitory effect of PEG2k-Fmoc-NLG is tested by an in vitro IDO assay. Briefly, HeLa cells areseeded in a 96-well plate at a cell density of 5000 cells per well and allowed to grow overnight. Recombin

12、anthuman IFN- is then added to each well with a final concentration of 50ng/mL. At the same time, variousconcentrations of PEG2k-Fmoc-NLG(L), PEG2k-Fmoc-NLG(S) or Navoximod (NLG919) (50nM-20M) areadded to the cells. After 48h of incubation, 150L of the supernatants per well is transferred to a new 9

13、6-wellplate. Seventy-five L of 30% trichloroacetic acid is added into each well and the mixture is incubated at50C for 30min to hydrolyse N-formylkynurenine to kynurenine. For colorimetric assay, supernatants aretransferred to a new 96-well plate, mixed with equal volume of Ehrlich reagent (2% p-dim

14、ethylamino-benzaldehyde w/v in glacial acetic acid), and incubated for 10min at RT. Reaction product is measured at2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE490nm by a plate reader 3.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 2Ad

15、ministration 2 Mice are anesthetized with 4% isoflurane, and the surgical plane of anesthesia is maintained with 2%isoflurane in oxygen. Mice are immobilized in a stereotactic frame for tumor implantation. Briefly, the skull isshaved and exposed with a 0.5 cm skin incision. With antiseptic technique

16、, 105 GL261 cells (suspended in 3L RPMI-1640) are injected at the following coordinates with respect to the bregma on the right side (antero-posterior, -2 mm; medio-lateral, 2 mm; dorso-ventral, 3 mm). This placement reproducibly yielded tumorgrowth in a paracortical area of the posterolateral right

17、 frontal lobe. Tumor-bearing mice are treated withcombinations of oral DL-1MT (2 mg/mL D-1MT mixed with 2 mg/mL L-1MT) in drinking water, D-1MT (4mg/mL) in drinking water, Navoximod (6 mg/mL) in drinking water, intraperitoneal cyclophosphamide,intraperitoneal temozolomide, and/or total-body radiatio

18、n (500 cGy from a 137Cs source), as detailed infigure legends. Mice are observed daily, and sacrificed when they became ill or moribund 2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Adv Sci (Weinh). 2019 Apr 18;6(12):1900327. Toxicol Appl Pharmacol. 2017 May 15;323:74-80.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Mario R. Mautino, et al. Abstract 491: NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibito