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

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 10; pp. 3460 - 3466
• Main Authors: Martínez González, Sonia, Hernández, Ana Isabel, Varela, Carmen, Rodríguez-Arístegui, Sonsoles, Lorenzo, Milagros, Rodríguez, Antonio, Rivero, Virginia, Martín, José Ignacio, Saluste, Carl Gustav, Ramos-Lima, Francisco, Cendón, Elena, Cebrián, David, Aguirre, Enara, Gomez-Casero, Elena, Albarrán, Maribel, Alfonso, Patricia, García-Serelde, Beatriz, Oyarzabal, Julen, Rabal, Obdulia, Mulero, Francisca, Gonzalez-Granda, Teresa, Link, Wolfgang, Fominaya, Jesús, Barbacid, Mariano, Bischoff, James R., Pizcueta, Pilar, Pastor, Joaquín
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-05-2012; Elsevier
• Subjects: Administration, Oral; Biological and medical sciences; Biological Availability; Cancer treatment; gene expression regulation; growth retardation; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Isoenzymes - antagonists & inhibitors; Medical sciences; mice; mutation; neoplasms; pharmacokinetics; Pharmacology. Drug treatments; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; phosphorylation; PI3K inhibitors; Positron-Emission Tomography; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; pyrazines; Pyrazines - administration & dosage; Pyrazines - pharmacokinetics; Pyrazines - pharmacology; signal transduction; therapeutics; Tomography, X-Ray Computed; PI3K inhibitors; Cancer treatment; Antineoplastic agent; Signal transduction; Enzyme; Transferases; Oral administration; Inhibitor; Bioavailability; Pharmacokinetics; 1-Phosphatidylinositol 3-kinase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.03.090

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 AKTSer473 phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-RasG12V oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition.