TEPP-46 - CAS 1221186-53-3
Catalog number: 1221186-53-3
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C17H16N4O2S2
Molecular Weight:
372.46
COA:
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Targets:
PDK-1
Description:
TEPP-46, an effective sensitizer of recombinant pyruvate kinase M2, has been found to decrease the formation of tumor in a mouse xenograft model. IC50: 92 nM (AC50).
Purity:
95%
Appearance:
Powder
Synonyms:
ML265; ML-265; ML 265; CID44246499; CID-44246499; CID 44246499; NCGC00186528; NCGC 00186528; NCGC-00186528; TEPP46; TEPP 46; TEPP-46; 6-[(3-aminophenyl)methyl]-4,6-dihydro-4-methyl-2-(methylsulfinyl)-5h-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one; ML265; TEPP 46; MLS006010294
Solubility:
DMSO: ≥ 31 mg/mL
Storage:
-20ºC Freeze
MSDS:
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Application:
TEPP-46 has been found to decrease the formation of tumor in a mouse xenograft model.
Shelf Life:
As supplied, 2 years from the QC date provided on the Certificate of Analysis, when stored properly
Quantity:
Milligrams-Grams
InChIKey:
ZWKJWVSEDISQIS-UHFFFAOYSA-N
InChI:
InChI=1S/C17H16N4O2S2/c1-20-13-7-14(25(2)23)24-16(13)12-8-19-21(17(22)15(12)20)9-10-4-3-5-11(18)6-10/h3-8H,9,18H2,1-2H3
Canonical SMILES:
CN1C2=C(C3=C1C(=O)N(N=C3)CC4=CC(=CC=C4)N)SC(=C2)S(=O)C
1.PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose.
Tee SS;Park JM;Hurd RE;Brimacombe KR;Boxer MB;Massoud TF;Rutt BK;Spielman DM Oncotarget. 2017 Jul 26;8(53):90959-90968. doi: 10.18632/oncotarget.19630. eCollection 2017 Oct 31.
Cancer metabolism has emerged as an increasingly attractive target for interfering with tumor growth. Small molecule activators of pyruvate kinase isozyme M2 (PKM2) suppress tumor formation but have an unknown effect on established tumors. We demonstrate that TEPP-46, a PKM2 activator, results in increased glucose consumption, providing the rationale for combining PKM2 activators with the toxic glucose analog, 2-deoxy-D-glucose (2-DG). Combination treatment resulted in reduced viability of a range of cell lines in standard cell culture conditions at concentrations of drugs that had no effect when used alone. This effect was replicated ;in vivo; on established subcutaneous tumors. We further demonstrated the ability to detect acute metabolic differences in combination treatment using hyperpolarized magnetic resonance spectroscopy (MRS). Combination treated tumors displayed a higher pyruvate to lactate ;13;C-label exchange 2 hr post-treatment. This ability to assess the effect of drugs non-invasively may accelerate the implementation and clinical translation of drugs that target cancer metabolism.
2.Pyruvate Kinase M2 Is Required for the Expression of the Immune Checkpoint PD-L1 in Immune Cells and Tumors.
Palsson-McDermott EM;Dyck L;Zasłona Z;Menon D;McGettrick AF;Mills KHG;O'Neill LA Front Immunol. 2017 Oct 13;8:1300. doi: 10.3389/fimmu.2017.01300. eCollection 2017.
Blocking interaction of the immune checkpoint receptor PD-1 with its ligand PD-L1 is associated with good clinical outcomes in a broad variety of malignancies. High levels of PD-L1 promote tumor growth by restraining CD8;+; T-cell responses against tumors. Limiting PD-L1 expression and function is therefore critical for allowing the development of antitumor immune responses and effective tumor clearance. Pyruvate kinase isoform M2 (PKM2) is also a key player in regulating cancer as well as immune responses. PKM2 catalyzes the final rate-limiting step of glycolysis. Furthermore, PKM2 as a dimer translocates to the nucleus, where it stimulates hypoxia-inducible factor 1α (Hif-1α) transactivation domain function and recruitment of p300 to the hypoxia response elements (HRE) of Hif-1α target genes. Here, we provide the first evidence of a role for PKM2 in regulating the expression of PD-L1 on macrophages, dendritic cells (DCs), T cells, and tumor cells. LPS-induced expression of PD-L1 in primary macrophages was inhibited by the PKM2 targeting compound TEPP-46. Furthermore, RNA silencing of PKM2 inhibited LPS-induced PD-L1 expression. This regulation occurs through direct binding of PKM2 and Hif-1α to HRE sites on the PD-L1 promoter.
3.Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/Pyruvate Kinase Muscle Axis.
Zhang H;Wang D;Li M;Plecitá-Hlavatá L;D'Alessandro A;Tauber J;Riddle S;Kumar S;Flockton A;McKeon BA;Frid MG;Reisz JA;Caruso P;El Kasmi KC;Ježek P;Morrell NW;Hu CJ;Stenmark KR Circulation. 2017 Dec 19;136(25):2468-2485. doi: 10.1161/CIRCULATIONAHA.117.028069. Epub 2017 Sep 26.
BACKGROUND: ;An emerging metabolic theory of pulmonary hypertension (PH) suggests that cellular and mitochondrial metabolic dysfunction underlies the pathology of this disease. We and others have previously demonstrated the existence of hyperproliferative, apoptosis-resistant, proinflammatory adventitial fibroblasts from human and bovine hypertensive pulmonary arterial walls (PH-Fibs) that exhibit constitutive reprogramming of glycolytic and mitochondrial metabolism, accompanied by an increased ratio of glucose catabolism through glycolysis versus the tricarboxylic acid cycle. However, the mechanisms responsible for these metabolic alterations in PH-Fibs remain unknown. We hypothesized that in PH-Fibs microRNA-124 (miR-124) regulates PTBP1 (polypyrimidine tract binding protein 1) expression to control alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2, resulting in an increased PKM2/PKM1 ratio, which promotes glycolysis and proliferation even in aerobic environments.;METHODS: ;Pulmonary adventitial fibroblasts were isolated from calves and humans with severe PH (PH-Fibs) and from normal subjects. PTBP1 gene knockdown was achieved via PTBP1-siRNA; restoration of miR-124 was performed with miR-124 mimic.
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