Identification of GNE-293, a potent and selective PI3K¦Ä inhibitor: Navigating in vitro genotoxicity while improving potency and selectivity

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• 作者：Brian S. Safina ; Zachary K. Sweeney ; Jun Li ; Bryan K. Chan ; Angelina Bisconte ; Diane Carrera ; Georgette Castanedo ; Michael Flagella ; Robert Heald ; Cristina Lewis ; Jeremy M. Murray ; Jim Nonomiya ; Jodie Pang ; Steve Price ; Karin Reif ; Laurent Salphati ; Eileen M. Seward ; Binqing Wei ; Daniel P. Sutherlin
• 关键词：PI3K ¦Ä ; PI3K isoform selectivity ; B-cell inhibition ; Genotox ; HCA ; MNT
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 September, 2013
• 年：2013
• 卷：23
• 期：17
• 页码：4953-4959
• 全文大小：2195 K

文摘

In an effort to identify potent and isoform selective inhibitors of PI3K¦Ä, GNE-293 (34) was identified. Inhibitor 2 was found to induce micronuclei formation in both the MNT and HCA in vitro assays. Compounds testing negative for genotoxicity were successfully identified through modifications of the 2-benzimidazole substituent and the methylene moiety to disrupt planarity. A variety of heteroatom linkers were explored to examine their effect on potency and isoform selectivity by restricting torsional angles to favor ligand interactions with PI3K¦Ä¡¯s Trp760. These modifications also resulted in an improved in vivo pharmacokinetic profile.