Identification of ETP-46321, a potent and orally bioavailable PI3K 伪, 未 inhibitor

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• 作者：Sonia Mart&iacute ; nez Gonzá ; lez^a ; Ana Isabel Herná ; ndez^a ; Carmen Varela^a ; Sonsoles Rodr&iacute ; guez-Ar&iacute ; stegui^a ; Milagros Lorenzo^a ; Antonio Rodr&iacute ; guez^a ; Virginia Rivero^a ; José ; Ignacio Mart&iacute ; n^a ; Carl Gustav Saluste^a ; Francisco Ramos-Lima^a ; Elena Cendó ; n^a ; David Cebriá ; n^a ; Enara Aguirre^a ; Elena Gomez-Casero^a ; Maribel Albarrá ; n^a ; Patricia Alfonso^a ; Beatriz Garc&iacute ; a-Serelde^a ; Julen Oyarzabal^a ; ^&dagger ; ; Obdulia Rabal^a ; ^&dagger ; ; Francisca Mulero^b ; Teresa Gonzalez-Granda^a ; Wolfgang Link^a ; Jesú ; s Fominaya^a ; Mariano Barbacid^c ; James R. Bischoff^a ; ^&Dagger ; ; Pilar Pizcueta^a ; Joaqu&iacute ; n Pastor^a ; ^{jpastor@cnio.es}
• 关键词：PI3K inhibitors ; Cancer treatment
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 May, 2012
• 卷：22
• 期：10
• 页码：3460-3466
• 文件大小：1735 K

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.