ETP-46321 - CAS 1252594-99-2
Catalog number: B0084-462342
Category: Inhibitor
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ETP-46321 is a potent and orally bioavailable PI3K α, δ inhibitor with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition.
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B0084-462342 300 mg $499 In stock
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Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
1.Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor.
Martínez González S1, Hernández AI, Varela C, Rodríguez-Arístegui S, Lorenzo M, Rodríguez A, Rivero V, Martín JI, Saluste CG, Ramos-Lima F, Cendón E, Cebrián D, Aguirre E, Gomez-Casero E, Albarrán M, Alfonso P, García-Serelde B, Oyarzabal J, Rabal O, Mule Bioorg Med Chem Lett. 2012 May 15;22(10):3460-6. doi: 10.1016/j.bmcl.2012.03.090. Epub 2012 Mar 29.
Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition.
2.Biological characterization of ETP-46321 a selective and efficacious inhibitor of phosphoinositide-3-kinases.
Granda TG1, Cebrián D, Martínez S, Anguita PV, López EC, Link W, Merino T, Pastor J, Serelde BG, Peregrina S, Palacios I, Albarran MI, Cebriá A, Lorenzo M, Alonso P, Fominaya J, López AR, Bischoff JR. Invest New Drugs. 2013 Feb;31(1):66-76. doi: 10.1007/s10637-012-9835-5. Epub 2012 May 24.
Inhibitors of PI3K signaling are of great therapeutic interest in oncology. The phosphoinositide-3-kinase signaling pathway is activated in a variety of solid and non-solid tumors. We have identified an imidazopyrazine derivative, ETP-46321, as a potent inhibitor of PI3Kα [Formula: see text]. The compound was 6 times less potent towards PI3Kδ and more than 200 and 60 times less potent at inhibiting PI3Kβ and PI3Kγ and did not significantly inhibit the related phosphoinositide-3-kinase-related protein kinase family kinases mTOR or DNA PK (IC(50)'s > 5 μM), or an additional 287 protein kinases that were screened. ETP-46321 inhibited PI3K signaling in treated tumor cell lines, induced cell cycle arrest and inhibited VEGF-dependent sprouting of HUVEC cells. The compound was anti-proliferative and synergized with both cytotoxic and targeted therapeutics. The compound induced a reduction in the phosphorylation of Akt in U87 MG xenografts after a single treatment.
3.ETP-46321, a dual p110α/δ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis.
Aragoneses-Fenoll L1, Montes-Casado M1, Ojeda G1, Acosta YY2, Herranz J2, Martínez S3, Blanco-Aparicio C3, Criado G4, Pastor J3, Dianzani U5, Portolés P6, Rojo JM7. Biochem Pharmacol. 2016 Apr 15;106:56-69. doi: 10.1016/j.bcp.2016.02.005. Epub 2016 Feb 13.
Class IA phosphoinositide 3-kinases (PI3Ks) are essential to function of normal and tumor cells, and to modulate immune responses. T lymphocytes express high levels of p110α and p110δ class IA PI3K. Whereas the functioning of PI3K p110δ in immune and autoimmune reactions is well established, the role of p110α is less well understood. Here, a novel dual p110α/δ inhibitor (ETP-46321) and highly specific p110α (A66) or p110δ (IC87114) inhibitors have been compared concerning T cell activation in vitro, as well as the effect on responses to protein antigen and collagen-induced arthritis in vivo. In vitro activation of naive CD4(+) T lymphocytes by anti-CD3 and anti-CD28 was inhibited more effectively by the p110δ inhibitor than by the p110α inhibitor as measured by cytokine secretion (IL-2, IL-10, and IFN-γ), T-bet expression and NFAT activation. In activated CD4(+) T cells re-stimulated through CD3 and ICOS, IC87114 inhibited Akt and Erk activation, and the secretion of IL-2, IL-4, IL-17A, and IFN-γ better than A66.
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CAS 1252594-99-2 ETP-46321

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