1. Combined Scaffold Evaluation and Systems‐Level Transcriptome‐Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes
- Author
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Miranda Burnette, Mayland Chang, Kevin X. Rodriguez, Erin N. Howe, Patricia M. Schnepp, Jennifer L. Meloche, Jayda E. Meisel, Emily P. Bacher, Jeremiah J. Zartman, Xuejuan Tan, Brandon L. Ashfeld, and Siyuan Zhang
- Subjects
Cyclopropanes ,Antineoplastic Agents ,Computational biology ,01 natural sciences ,Biochemistry ,Article ,Transcriptome ,Structure-Activity Relationship ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Spiro Compounds ,RNA, Neoplasm ,General Pharmacology, Toxicology and Pharmaceutics ,Cell Proliferation ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Drug discovery ,Organic Chemistry ,Cancer ,Ribosomal RNA ,medicine.disease ,Small molecule ,Oxindoles ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Mechanism of action ,Molecular Medicine ,Scaffold Evaluation ,Drug Screening Assays, Antitumor ,medicine.symptom ,Ribosomes ,Function (biology) - 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.
- Published
- 2019
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