Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor

被引：23

作者：

Martinez Gonzalez, Sonia ^{[1
]}

Isabel Hernandez, Ana ^{[1
]}

Varela, Carmen ^{[1
]}

Rodriguez-Aristegui, Sonsoles ^{[1
]}

Lorenzo, Milagros ^{[1
]}

Rodriguez, Antonio ^{[1
]}

Rivero, Virginia ^{[1
]}

Ignacio Martin, Jose ^{[1
]}

Gustav Saluste, Carl ^{[1
]}

Ramos-Lima, Francisco ^{[1
]}

Cendon, Elena ^{[1
]}

Cebrian, David ^{[1
]}

Aguirre, Enara ^{[1
]}

Gomez-Casero, Elena ^{[1
]}

Albarran, Maribel ^{[1
]}

Alfonso, Patricia ^{[1
]}

Garcia-Serelde, Beatriz ^{[1
]}

Oyarzabal, Julen ^{[1
]}

Rabal, Obdulia ^{[1
]}

Mulero, Francisca ^{[2
]}

Gonzalez-Granda, Teresa ^{[1
]}

Link, Wolfgang ^{[1
]}

Fominaya, Jesus ^{[1
]}

Barbacid, Mariano ^{[3
]}

Bischoff, James R. ^{[1
]}

Pizcueta, Pilar ^{[1
]}

Pastor, Joaquin ^{[1
]}

机构：

[1] Spanish Natl Canc Res Ctr CNIO, Expt Therapeut Programme, E-28029 Madrid, Spain

[2] Spanish Natl Canc Res Ctr CNIO, Mol Imaging Unit, E-28029 Madrid, Spain

[3] Spanish Natl Canc Res Ctr CNIO, Mol Onclol Programme, E-28029 Madrid, Spain

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 10期

关键词：

PI3K inhibitors; Cancer treatment; PHOSPHOINOSITIDE; 3-KINASES; KINASE INHIBITOR; PIK3CA GENE; MUTATIONS; ONCOGENE; DISCOVERY; OVARIAN; CANCER; FAMILY; PTEN;

D O I：

10.1016/j.bmcl.2012.03.090

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3460 / 3466

页数：7

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