IDO Pathway inhibitor


CAS No. : 110117-83-4

IDO Pathway inhibitor,110117-83-4
Product Details
For research use only. Not Intended for Therapeutic Use!
Cat No:I000417
Synonyms:(E)-3/'-methyl-3/'/'-styryl-3,2/':5/',2/'/':5/'/',3/'/'/'-quaterpyridine
Molecular Formula:C₁₂H₁₄N₂O₂
Molecular Weight:218.25
Target:IDO
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Appearance:Solid powder
Purity: > 98%
Cat No:I000417
Cas No:110117-83-4
Product-Name:IDO Pathway inhibitor
MDL No:MFCD00274271
InChI:InChI=1S/C12H14N2O2/c1-14-7-8(6-10(13)12(15)16)9-4-2-3-5-11(9)14/h2-5,7,10H,6,13H2,1H3,(H,15,16)/t10-/m1/s1
InChIKey:ZADWXFSZEAPBJS-SNVBAGLBSA-N
SMILES:CN1C=C(C2=CC=CC=C21)CC(C(=O)O)N

Indoximod(cas# 110117-83-4) is an IDO pathway inhibitor, and reverses IDO-mediated immune suppression.
The overexpression of IDO in tumors and tumor-draining lymph nodes induces immune tolerance and enhances tumor growth in vivo. 1-methyl-D-Tryptophan is an inhibitor of IDO (IC50 = 7 μM) that is effective in vivo.

1. Oncotarget. 2016 Apr 19;7(16):22928-38. doi: 10.18632/oncotarget.8216.

A phase I study of indoximod in patients with advanced malignancies.

Soliman HH(1), Minton SE(1), Han HS(1), Ismail-Khan R(1), Neuger A(1), Khambati F(1), Noyes D(1), Lush R(1), Chiappori AA(1), Roberts JD(2), Link C(3), Vahanian NN(3), Mautino M(3), Streicher H(4), Sullivan DM(1), Antonia SJ(1).
Author information:
(1)H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. (2)Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA. (3)NewLink Genetics Inc., Ames, Iowa, USA. (4)Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.
PURPOSE: Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates.
EXPERIMENTAL DESIGN: Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. RESULTS: In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (~12 μM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels.
CONCLUSIONS: Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed.

2. Oncotarget. 2014 Sep 30;5(18):8136-46.

A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors.

Soliman HH(1), Jackson E(2), Neuger T(1), Dees EC(3), Harvey RD(4), Han H(1), Ismail-Khan R(1), Minton S(1), Vahanian NN(5), Link C(5), Sullivan DM(1), Antonia S(1).
Author information:
(1)H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. (2)University of South Florida, Tampa, FL. (3)University of North Carolina/Lineberger Cancer Center, Chapel Hill, NC. (4)Winship Cancer Institute of Emory University, Atlanta, GA. (5)NewLink Genetics Inc, Ames, IA.
BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to create a state of immunosuppression. Indoximod is an IDO pathway inhibitor. Preclinical studies demonstrated that indoximod combined with chemotherapy was synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed to study the combination of docetaxel and indoximod.
METHODS: Docetaxel was administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2 for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO twice daily continuously for levels 1-5, respectively. Serum drug levels were measured.
RESULTS: Twenty-seven patients were treated, with 22 evaluable for response. DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug interactions were noted.
CONCLUSIONS: Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.

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