Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo.
AuthorsStenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, Raymond J, Toews J, Wu J, Ogden N, MacRury T, Szabo C,
JournalBr J Pharmacol
PubMed ID23121445
The SH2-containing inositol-5'-phosphatase 1 (SHIP1) metabolizes PI(3,4,5)P3 to PI(3,4)P2. SHIP1-deficient mice exhibit progressive inflammation. Pharmacological activation of SHIP1 is emerging as a potential therapy for pulmonary inflammatory diseases. Here we characterize the efficacy of AQX-1125, a small-molecule SHIP1 activator currently in clinical development. The effects of AQX-1125 were tested in ... More
Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data.
AuthorsChen WW, Schoeberl B, Jasper PJ, Niepel M, Nielsen UB, Lauffenburger DA, Sorger PK,
JournalMol Syst Biol
PubMed ID19156131
The ErbB signaling pathways, which regulate diverse physiological responses such as cell survival, proliferation and motility, have been subjected to extensive molecular analysis. Nonetheless, it remains poorly understood how different ligands induce different responses and how this is affected by oncogenic mutations. To quantify signal flow through ErbB-activated pathways we ... More
Pharmacokinetic-pharmacodynamic modeling of tumor growth inhibition and biomarker modulation by the novel phosphatidylinositol 3-kinase inhibitor GDC-0941.
AuthorsSalphati L, Wong H, Belvin M, Bradford D, Edgar KA, Prior WW, Sampath D, Wallin JJ,
JournalDrug Metab Dispos
PubMed ID20538720
The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation, by activation or transforming mutations of the p110alpha subunit, is associated with the development of many cancers. 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) is a novel small molecule inhibitor of PI3K currently being evaluated in the clinic as ... More