Combined Scaffold Evaluation and Systems-Level Transcriptome-Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes

Kevin X. Rodriguez, Erin N. Howe, Emily P. Bacher, Miranda Burnette, Jennifer L. Meloche, Jayda Meisel, Patricia Schnepp, Xuejuan Tan, Mayland Chang, Jeremiah Zartman, Siyuan Zhang, Brandon L. Ashfeld

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

With evolutionary drug resistance impacting efforts to treat disease, the need for small molecules that exhibit novel molecular mechanisms of action is paramount. In this study, we combined scaffold-directed synthesis with a hybrid experimental and transcriptome analysis to identify bis-spirooxindole cyclopropanes that inhibit cancer cell proliferation through disruption of ribosomal function. These findings demonstrate the value of an integrated, biologically inspired synthesis and assay strategy for the accelerated identification of first-in-class cancer therapeutic candidates.

Original languageEnglish (US)
Pages (from-to)1653-1661
Number of pages9
JournalChemMedChem
Volume14
Issue number18
DOIs
StatePublished - Sep 18 2019
Externally publishedYes

Keywords

  • drug discovery
  • mechanism of action
  • natural products
  • spirooxindoles
  • transcriptome network

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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