Design, synthesis and biological evaluation of Pontin ATPase inhibitors through a molecular docking approach

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 11; pp. 2512 - 2516
• Main Authors: Elkaim, Judith, Lamblin, Marc, Laguerre, Michel, Rosenbaum, Jean, Lestienne, Patrick, Eloy, Laure, Cresteil, Thierry, Felpin, François-Xavier, Dessolin, Jean
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.06.2014; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; ATPase activity; ATPases Associated with Diverse Cellular Activities; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - metabolism; Cell Proliferation - drug effects; Chemical Sciences; Chemistry; Chemistry, Medicinal; Chemistry, Organic; DNA Helicases - antagonists & inhibitors; DNA Helicases - metabolism; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzymatic assay; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HCT116 Cells; HL-60 Cells; Humans; KB Cells; Life Sciences & Biomedicine; MCF-7 Cells; Models, Molecular; Molecular docking; Molecular Structure; Organic chemistry; Pharmacology & Pharmacy; Physical Sciences; Pontin; Science & Technology; Small-molecule inhibitor; Structure-Activity Relationship; Enzymatic assay; Pontin; ATPase activity; Small-molecule inhibitor; Molecular docking; TRANSFORMATION; COMPLEX; TIP49; REPTIN; RUVB-LIKE PROTEIN; INDUCTION; IDENTIFICATION; SCORING FUNCTION; DNA HELICASE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.04.003

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.