Carol Khodier
Broad Institute
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Publication
Featured researches published by Carol Khodier.
Bioorganic & Medicinal Chemistry Letters | 2013
Longqin Hu; Sadagopan Magesh; Lin Chen; Lili Wang; Tim Lewis; Yu Chen; Carol Khodier; Daigo Inoyama; Lesa J. Beamer; Thomas J. Emge; Jian Shen; John E. Kerrigan; Ah-Ng Tony Kong; Sivaraman Dandapani; Michelle Palmer; Stuart L. Schreiber; Benito Munoz
A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure-activity relationships support its use as a lead for our ongoing optimization.
Cell Metabolism | 2015
Sean M. Burns; Amedeo Vetere; Deepika Walpita; Vlado Dančík; Carol Khodier; Jose R. Perez; Paul A. Clemons; Bridget K. Wagner; David Altshuler
Defects in insulin secretion play a central role in the pathogenesis of type 2 diabetes, yet the mechanisms driving beta-cell dysfunction remain poorly understood, and therapies to preserve glucose-dependent insulin release are inadequate. We report a luminescent insulin secretion assay that enables large-scale investigations of beta-cell function, created by inserting Gaussia luciferase into the C-peptide portion of proinsulin. Beta-cell lines expressing this construct cosecrete luciferase and insulin in close correlation, under both standard conditions or when stressed by cytokines, fatty acids, or ER toxins. We adapted the reporter for high-throughput assays and performed a 1,600-compound pilot screen, which identified several classes of drugs inhibiting secretion, as well as glucose-potentiated secretagogues that were confirmed to have activity in primary human islets. Requiring 40-fold less time and expense than the traditional ELISA, this assay may accelerate the identification of pathways governing insulin secretion and compounds that safely augment beta-cell function in diabetes.
Nature Chemical Biology | 2016
Cecilia Lopez-Sambrooks; Shiteshu Shrimal; Carol Khodier; Daniel P. Flaherty; Natalie Rinis; Jonathan Charest; Ningguo Gao; Peng Zhao; Lance Wells; Tim Lewis; Mark A. Lehrman; Reid Gilmore; Jennifer E. Golden; Joseph N. Contessa
Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high-throughput screen and lead-compound-optimization campaign that delivered a cell-permeable inhibitor, NGI-1. NGI-1 targets oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small-cell lung cancer cells, NGI-1 blocks cell-surface localization and signaling of the epidermal growth factor receptor (EGFR) glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or fibroblast growth factor, FGFR) for survival. In these cell lines, OST inhibition causes cell-cycle arrest accompanied by induction of p21, autofluorescence, and cell morphology changes, all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor-tyrosine-kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells.
Archive | 2013
Lili Wang; Tim Lewis; Yan-Ling Zhang; Carol Khodier; Sadagopan Magesh; Lin Chen; Daigo Inoyama; Yu Chen; Jing Zhen; Longqin Hu; Lesa J. Beamer; Patrick W. Faloon; Sivaraman Dandapani; Jose R. Perez; Benito Munoz; Michelle Palmer; Stuart L Schreiber
Archive | 2014
Carol Khodier; Lynn VerPlank; Partha Nag; Jun Pu; Jacqueline Wurst; Tatiana Pilyugina; Chris Dockendorff; Christine N. Galinski; Alissa A. Scalise; Freda Passam; Lotte van Hessem; James Dilks; Daniel R. Kennedy; Robert Flaumenhaft; Michelle Palmer; Sivaraman Dandapani; Benito Munoz; Stuart L. Schrieber
Archive | 2014
Carol Khodier; Lynn VerPlank; Partha Nag; Jun Pu; Jacqueline Wurst; Tatiana Pilyugina; Chris Dockendorff; Christine N. Galinski; Alissa A. Scalise; Freda Passam; Lotte van Hessem; James Dilks; Daniel R. Kennedy; Robert Flaumenhaft; Michelle Palmer; Sivaraman Dandapani; Benito Munoz; Stuart L. Schrieber
Archive | 2014
Carol Khodier; Lynn VerPlank; Partha Nag; Jun Pu; Jacqueline Wurst; Tatiana Pilyugina; Chris Dockendorff; Christine N. Galinski; Alissa A. Scalise; Freda Passam; Lotte van Hessem; James Dilks; Daniel R. Kennedy; Robert Flaumenhaft; Michelle Palmer; Sivaraman Dandapani; Benito Munoz; Stuart L. Schrieber
Archive | 2014
Carol Khodier; Lynn VerPlank; Partha Nag; Jun Pu; Jacqueline Wurst; Tatiana Pilyugina; Chris Dockendorff; Christine N. Galinski; Alissa A. Scalise; Freda Passam; Lotte van Hessem; James Dilks; Daniel R. Kennedy; Robert Flaumenhaft; Michelle Palmer; Sivaraman Dandapani; Benito Munoz; Stuart L. Schrieber
Archive | 2014
Carol Khodier; Lynn VerPlank; Partha Nag; Jun Pu; Jacqueline Wurst; Tatiana Pilyugina; Chris Dockendorff; Christine N. Galinski; Alissa A. Scalise; Freda Passam; Lotte van Hessem; James Dilks; Daniel R. Kennedy; Robert Flaumenhaft; Michelle Palmer; Sivaraman Dandapani; Benito Munoz; Stuart L. Schrieber
Archive | 2014
Carol Khodier; Lynn VerPlank; Partha Nag; Jun Pu; Jacqueline Wurst; Tatiana Pilyugina; Chris Dockendorff; Christine N. Galinski; Alissa A. Scalise; Freda Passam; Lotte van Hessem; James Dilks; Daniel R. Kennedy; Robert Flaumenhaft; Michelle Palmer; Sivaraman Dandapani; Benito Munoz; Stuart L. Schrieber