An Unusual Intramolecular Halogen Bond Guides Conformational Selection
PIK-75 is a phosphoinositide-3-kinase (PI3K) α-isoform-selective inhibitor with high potency. Although published structure–activity relationship data show the importance of the NO2 and the Br substituents in PIK-75, none of the published studies could correctly determine the underlying reason for their importance. In this publication, we report the first X-ray crystal structure of PIK-75 in complex with the kinase GSK-3β. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3β that is likely stabilized by an atypical intramolecular Br???NO2 halogen bond. NMR and MD simulations show that this conformation presumably also exists in solution and leads to a binding-competent preorganization of the PIK-75 molecule, thus explaining its high potency. We therefore suggest that the site-specific incorporation of halogen bonds could be generally used to design conformationally restricted bioactive substances with increased potencies.
Tesch, Roberta,Becker, Christian,Müller, Matthias Philipp,Beck, Michael Edmund,Quambusch, Lena,Getlik, Matth?us,Lategahn, Jonas,Uhlenbrock, Niklas,Costa, Fanny Nascimento,Polêto, Marcelo D.,Pinheiro, Pedro de Sena Murteira,Rodrigues, Daniel Alencar,Sant'Anna, Carlos Mauricio R.,Ferreira, Fabio Furlan,Verli, Hugo,Fraga, Carlos Alberto Manssour,Rauh, Daniel
supporting information
p. 9970 - 9975
(2018/07/31)
Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110α inhibitors
We have previously reported the imidazo[1,2-a]pyridine derivative 4 as a novel p110α inhibitor; however, although 4 is a potent inhibitor of p110α enzymatic activity and tumor cell proliferation in vitro, it is unstable in solution and ineffective in vivo
Hayakawa, Masahiko,Kawaguchi, Ken-ichi,Kaizawa, Hiroyuki,Koizumi, Tomonobu,Ohishi, Takahide,Yamano, Mayumi,Okada, Minoru,Ohta, Mitsuaki,Tsukamoto, Shin-ichi,Raynaud, Florence I.,Parker, Peter,Workman, Paul,Waterfield, Michael D.
p. 5837 - 5844
(2008/03/18)
Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110α inhibitors
A series of 2-methyl-5-nitrobenzenesulfonohydrazides were prepared and evaluated as inhibitors of PI3K. An isoquinoline derivative shows good selectivity for the p110α isoform over p110β and p110δ, and also demonstrates good in vitro activity in a cell pr
Kendall, Jackie D.,Rewcastle, Gordon W.,Frederick, Raphael,Mawson, Claire,Denny, William A.,Marshall, Elaine S.,Baguley, Bruce C.,Chaussade, Claire,Jackson, Shaun P.,Shepherd, Peter R.
p. 7677 - 7687
(2008/03/14)
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