자료유형  

 학위논문

Control Number  

0016932293

International Standard Book Number  

9798379612566

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Miyamoto, David.

Publication, Distribution, etc. (Imprint  

[S.l.] : Harvard University., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(497 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

General Note  

Includes supplementary digital materials.

General Note  

Advisor: Woo, Christina.

Dissertation Note  

Thesis (Ph.D.)--Harvard University, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Immunomodulatory drugs (IMiDs) function as molecular glues between the E3 ligase substrate receptor cereblon (CRBN) and protein substrates. The formation of this ternary complex results in the substrates' ubiquitination and proteasomal degradation. The field of targeted protein degradation has extensively utilized this unique mechanism of action to degrade various protein substrates to study biological processes and for therapeutic applications. Here, using a structure-guided approach, I develop novel small molecules based on the IMiDs to degrade various proteins implicated in disease.In chapter 1, I discuss the history of the IMiDs and describe the structural basis for their substrate scope. I review the major proteins that are degraded by the IMiDs and how they were discovered and the structural basis for the IMiD's engagement of neosubstrates. I also discuss the ongoing efforts to degrade these substrates and their therapeutic applications in various diseases.In chapter 2, I report the medicinal chemistry efforts to develop a small molecule that degrades the transcription factor Ikaros zinc finger protein 2 (IKZF2) and casein kinase 1 alpha (CK1α) both of which are targets in acute myeloid leukemia (AML). I discuss the structural basis for changing the selectivity of the IMiD lenalidomide to degrade IKZF2 and describe the small library of molecules based on its scaffold that I synthesized. I then detail the extensive medicinal chemistry efforts to optimize IKZF2 degradation to afford lead compound 35. I show that 35 additionally degrades CK1α and describe efforts to optimize 35 for solubility and metabolic stability. These efforts resulted in degrader 77 which potently degrades IKZF2 and CK1α and shows cell killing activity in AML and ovarian cancer cell lines.In chapter 3 I report the use of 35 and 77 in the context of AML. I report that 35 and 77 degrade IKZF2 and CK1α across multiple AML cell lines and induce apoptosis and differentiation. I then describe the validation of these molecules as molecular glues and show using a high throughput screen that they are selective against certain cancer types including AML. I then report the phenotypic effects of IKZF2 and CK1α degradation separately and find that IKZF2 degradation leads to differentiation while CK1α degradation leads to apoptosis, cell cycle arrest, and differentiation. Finally, I report the use of 35 and 77 in vivo in various AML models and show that 77 treatment delays AML disease progression and nearly double the lifespan of mice with AML.Finally, in chapter 4 I describe efforts to develop chemical tools to study small molecule-protein interactions. While not directly related to protein degradation with molecular glues, this chapter highlights the ability of chemical tools to reveal structural insights into small molecule-protein interactions such as those discussed in previous chapters. I describe the development and optimization of a cleavable biotin picolyl azide probe that can be used to identify small molecule binding sites. Using this probe, I report a novel binding site of celecoxib on prostaglandin E synthase.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Pharmaceutical sciences.

Subject Added Entry-Topical Term  

Immunology.

Index Term-Uncontrolled  

Immunomodulatory drugs

Index Term-Uncontrolled  

Proteasomal degradation

Index Term-Uncontrolled  

Metabolic stability

Index Term-Uncontrolled  

Molecular glue degraders

Index Term-Uncontrolled  

Therapeutic agents

Index Term-Uncontrolled  

Chemical tools

Added Entry-Corporate Name  

Harvard University Chemistry and Chemical Biology

Host Item Entry  

Dissertations Abstracts International. 84-12B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:641815