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Dissertation/Thesis Abstract

Small-molecule probes to explore cancer
by Schaefer, Giannina Ines, Ph.D., Harvard University, 2014, 218; 3627119
Abstract (Summary)

Small molecules play important roles in therapeutics and drug discovery. Significant progress has been made by the chemical biology community to discover small-molecule probes to explore biological processes and to treat disease. This thesis describes both the discovery of novel probes for the Hedgehog (Hh) pathway and the application of small molecules in identifying cancer dependencies.

In a phenotypic screen for inhibitors of Hh signaling, a pathway sometimes deregulated in cancer, several previously annotated molecules were identified that, in addition to their original targets, were shown to have activity in this pathway. Furthermore, two potent small-molecule inhibitors, BRD50837 and BRD9526, were discovered. Analysis of structure-activity relationships (SAR) demonstrated striking stereochemistry-based SAR. This feature suggested a specific and selective interaction of these compounds with their cellular target(s). Further studies revealed that their mechanism of action displayed similarities to that of cyclopamine, a commonly used Hh probe that targets the Smoothened receptor, and yet differed strikingly in other aspects. Early insights into the probes' mechanisms of action shed light onto the nature of these novel compounds.

To advance the application of small molecules in cancer, an unbiased screen was performed using 242 genomically characterized cancer cell lines (CCLs) that were profiled using a set of 354 small molecules to discover novel oncogene and non-oncogene dependencies. Enrichment correlations between small-molecule sensitivity and genetic features were calculated. This allowed for known dependencies to be confirmed and generated several novel hypotheses. A public resource was created based on these efforts (

To address the challenge of interpreting genomic alteration/compound sensitivity relationships, genomic characterizations were prioritized using recurrent mutations, overlap with patient data, and annotation of fusion genes. This prioritized approach demonstrated that small-molecule sensitivity can be differential across mutations in the same gene, and allowed for identification of novel and specific dependencies. For example, pan- and PI3K-α-specific inhibitors appear to be more potent in PIK3CA E542K-mutated CCLs than other PIK3CA-mutated CCLs.

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Indexing (document details)
Advisor: Schreiber, Stuart L.
Commitee: Kahne, Daniel, Saghatelian, Alan
School: Harvard University
Department: Chemistry and Chemical Biology
School Location: United States -- Massachusetts
Source: DAI-B 75/10(E), Dissertation Abstracts International
Subjects: Biochemistry
Keywords: Cancer, Cancer dependencies, Hedgehog signaling, Small-molecule probes
Publication Number: 3627119
ISBN: 978-1-321-02238-4
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