Synthesis of Proteolysis Targeting Chimera Components with Pedagogical Applications for the Teaching–Research Nexus
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Zinsli, Zachary Tyler
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CitationZinsli, Zachary Tyler. 2021. Synthesis of Proteolysis Targeting Chimera Components with Pedagogical Applications for the Teaching–Research Nexus. Master's thesis, Harvard University Division of Continuing Education.
AbstractProteolysis targeting chimeras (PROTACs) exploit endogenous cellular ubiquitination mechanisms to selectively degrade proteins by initiating complexation between ubiquitin ligases and target substrates. Immunomodulatory imide drugs (IMiDs) activate cullin-ring E3-ubiquitination pathways and, when covalently linked to a protein inhibitor, form PROTACs, capable of the downregulation of target proteins by proximally tagging substrates for degradation by the proteasome. The heterobifunctionality of PROTACs is of growing pharmacological interest in posttranslational therapies for diseases with ectopic protein expression, while the diversity of their components makes them an ideal pedagogical tool in chemical biology and synthesis education. The purpose of this research was to synthesize a library of small-molecule components of PROTACs to be later appended and tested for degradation efficacy. Given the stereospecific effects of IMiDs, coupled with their susceptibility to rapid epimerization in physiological conditions, I also seek to investigate chiral stabilization and subsequent PROTAC efficacy by selectively deuterating the IMiD chiral center, which will then be enantiomerically separated prior to inhibitor linking. Here I report on the synthesis of IMiDs (±)-thalidomide, (±)-pomalidomide, (±)-4-hydroxylenalidomide, their respective isotopologues with deuterium incorporation at the chiral center, and the bromodomain and extra-terminal domain (BET) inhibitor, JQ1. Synthesis of heterobifunctional components was used as the vehicle for the development of enhanced peer-to-peer and inquiry-based learning techniques to lay the groundwork for sustained, multifaceted, undergraduate curricular research projects that offer diverse avenues for student investigations and contributions to current, relevant research.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37367707
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