Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-Sparing Phosphoinositide 3-Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity

Citations Over TimeTop 10% of 2013 papers

Abstract

Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.

Related Papers

• → FoxO Transcription Factors Promote AKT Ser473 Phosphorylation and Renal Tumor Growth in Response to Pharmacologic Inhibition of the PI3K–AKT Pathway(2014)162 cited
• → Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects(2013)21 cited
• → Virtual Docking Screening and QSAR Studies to Explore PI3K and mTOR Inhibitors Acting on AKT in Cancers(2020)1 cited
• → Solanine Interferes with AKT/p-AKT and PI3K/p-PI3K Pathway to Inhibit HIF and Destroy Cell Energy Metabolism(2021)1 cited
• → Solanine Interferes With AKT/p-AKT and PI3K/ p-PI3K to Inhibit HIF and Destroy Cell Energy Metabolism(2021)