Design, synthesis and biological evaluation of Pontin ATPase inhibitors through a molecular docking approach.
A virtual screening strategy, through molecular docking, for the elaboration of an electronic library of Pontin inhibitors has resulted in the identification of two original scaffolds. The chemical synthesis of four candidates allowed extensive biological evaluations for their anticancer activity. Two compounds displayed an effect on Pontin ATPase activity, and one of them also exhibited a noticeable effect on cell growth. Further biological studies revealed that the most active compound induced apoptotic cell death together with necrosis, this latter effect being likely related to the cellular balance of ATP regulation.
Université de Bordeaux, CNRS UMR 5248, CBMN, IECB, 2 rue Robert Escarpit, 33607 Pessac, France.
Judith
J
Elkaim
Université de Bordeaux, CNRS UMR 5248, CBMN, IECB, 2 rue Robert Escarpit, 33607 Pessac, France.
Marc
M
Lamblin
Université de Bordeaux, CNRS UMR 5248, CBMN, IECB, 2 rue Robert Escarpit, 33607 Pessac, France.
Michel
M
Laguerre
Physiopathologie du Cancer du Foie, INSERM U1053-Université de Bordeaux, 146 rue Léo Saignat, F-33076 Bordeaux Cedex, France.
Jean
J
Rosenbaum
Physiopathologie du Cancer du Foie, INSERM U1053-Université de Bordeaux, 146 rue Léo Saignat, F-33076 Bordeaux Cedex, France.
Patrick
P
Lestienne
Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
Laure
L
Eloy
Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
Thierry
T
Cresteil
Université de Nantes, CNRS UMR 6230, CEISAM, UFR des Sciences et des Techniques, 2 rue de la Houssinière, 44322 Nantes Cedex 3, France. Electronic address: fx.felpin@univ-nantes.fr.
François-Xavier
FX
Felpin
Université de Bordeaux, CNRS UMR 5248, CBMN, IECB, 2 rue Robert Escarpit, 33607 Pessac, France. Electronic address: j.dessolin@iecb.u-bordeaux.fr.
Jean
J
Dessolin
D000074183:ATPases Associated with Diverse Cellular Activities; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D018922:HL-60 Cells; D006801:Humans; D007624:KB Cells; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C486549:RUVBL1 protein, human
ATPase activity; Enzymatic assay; Molecular docking; Pontin; Small-molecule inhibitor