Han, Wooseok, Menezes, Daniel L., Xu, Yongjin, Knapp, Mark, Elling, Robert, Burger, Matthew, Ni, Zhi-Jie, Smith, Aaron, Lan, Jiong, Pick, Teresa, Verhagen, Joel, Huh, Kay, Merritt, Hanne, Chan, John, Kaufman, Susan, Voliva, Charles F. and Pecchi, Sabina (2016) Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model. Bioorg. Med. Chem. Lett., 26 (3). pp. 742-746. ISSN 0960894X

Abstract

Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5’-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5’-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6’-Alkoxy 5’-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6’-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.

Item Type:	Article
Date Deposited:	27 Apr 2016 23:45
Last Modified:	27 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/27404