5FI4

Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model

Summary for 5FI4

• Entry DOI: 10.2210/pdb5fi4/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, GLYCEROL, ... (5 entities in total)
• Functional Keywords: lipid kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 164503.73

Authors

Elling, R.A.,Knapp, M.S.,Han, W.,Daniel, L.M.,Xy, Y.,Burger, M.T.,Ni, Z.,Smith, A.,Lan, J.,Williams, T.,Verhagen, J.,Huh, K.,Merritt, H.,Chan, J.,Kaufman, S.,Voliva, C.F.,Pecchi, S. (deposition date: 2015-12-22, release date: 2016-02-03, Last modification date: 2024-03-06)

Primary citation

Han, W.,Menezes, D.L.,Xu, Y.,Knapp, M.S.,Elling, R.,Burger, M.T.,Ni, Z.J.,Smith, A.,Lan, J.,Williams, T.E.,Verhagen, J.,Huh, K.,Merritt, H.,Chan, J.,Kaufman, S.,Voliva, C.F.,Pecchi, S.
Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model.
Bioorg.Med.Chem.Lett., 26:742-746, 2016

PubMed 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 a 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.

PubMed: 26774655
DOI: 10.1016/j.bmcl.2016.01.003

Experimental method

X-RAY DIFFRACTION (2.5 Å)