title: A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton.
abstract: Natural product-inspired libraries of molecules with diverse architectures have evolved as one of the most useful tools for discovering lead molecules for drug discovery. In comparison to conventional combinatorial libraries, these molecules have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of molecules. From a successful DOS campaign of a natural product-inspired library, recently a small molecule with spiroindoline motif was identified as a potent anti-breast cancer compound. Herein we report the subcellular studies performed for this molecule on breast cancer cells. Our investigation revealed that it repositions microtubule cytoskeleton and displaces AKAP9 located at the microtubule organization centre. DNA ladder assay and cell cycle experiments further established the molecule as an apoptotic agent. This work further substantiated the amalgamation of DOS-phenotypic screening-sub-cellular studies as a consolidated blueprint for the discovery of potential pharmaceutical drug candidates.
authors.affiliation: Brain Metastasis and NeuroVascular Disease Modeling Lab, Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, NCR, India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, NH-91, G.B.Nagar, Tehsil Dadri, UP, 201314, India.
authors.forename: Santanu
authors.initials: S
authors.lastname: Hati
authors.affiliation: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, NH-91, G.B.Nagar, Tehsil Dadri, UP, 201314, India.
authors.forename: Parthapratim
authors.initials: P
authors.lastname: Munshi
authors.affiliation: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, NH-91, G.B.Nagar, Tehsil Dadri, UP, 201314, India.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Sen
authors.affiliation: Brain Metastasis and NeuroVascular Disease Modeling Lab, Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, NCR, India. Seema.sehrawat@snu.edu.in.|Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA. Seema.sehrawat@snu.edu.in.
authors.forename: Seema
authors.initials: S
authors.lastname: Sehrawat
authors.affiliation: Host Pathogen Interactions and Disease modeling Group, Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, NH-91, G.B.Nagar, Tehsil Dadri, UP, 201314, India. shailja.singh@snu.edu.in.|Special Centre for Molecular Medicine, JNU, New Delhi, India. shailja.singh@snu.edu.in.
authors.forename: Shailja
authors.initials: S
authors.lastname: Singh
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects; D015394:Molecular Structure; D021381:Protein Transport / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054758:A Kinase Anchor Proteins; C119719:AKAP9 protein, human; D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D007211:Indoles; D054852:Small Molecule Libraries
keywords: AKAP9; Breast cancer; Cell migration; Cytoskeleton; DOS; Spiroindolines; Tubulin