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

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.

SUBMITTER: Rodriguez KX

PROVIDER: S-EPMC6750968 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Rodriguez Kevin X KX Howe Erin N EN Bacher Emily P EP Burnette Miranda M Meloche Jennifer L JL Meisel Jayda J Schnepp Patricia P Tan Xuejuan X Chang Mayland M Zartman Jeremiah J Zhang Siyuan S Ashfeld Brandon L BL

ChemMedChem 20190701 18

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 strate ...[more]

PMID: 31140738

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