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Eukaryotic initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF), promotes protein synthesis by charging translation initiation factor 2 (eIF2) with GTP. Stress-induced phosphorylation of eIF2 on its α-subunit [eIF2(αP)] inhibits this reaction triggering a protective Integrated Stress Response (ISR). A DNA-encoded chemical library (DEL) screen for modulators of eIF2B, led to the identification of a chemical series that stabilises the inactive state of eIF2B, stimulating the ISR. Cryo-EM of compound-bound eIF2B reveals a conformational switch to the inactive state engaged by eIF2(αP). In cells, compound activity is sensitive to eIF2’s phosphorylation state and to a competing eIF2B ligand (ISRIB) that activates the GEF allosterically. These findings establish the feasibility of targeting eIF2B with a drug-like allosteric inhibitor, that serves as an ISR activator (ISRAC), paving the way to explore the therapeutic potential of eIF2B-directed ISR activation. Protein synthesis is tightly regulated by the integrated stress response, but therapeutic activation remains challenging. Here, the authors identify a drug‑like allosteric inhibitor, an ISRAC, that stabilises inactive eIF2B, mimicking stress‑induced eIF2α phosphorylation to activate the ISR, establishing eIF2B as a tractable target for ISR modulation.

This thesis describes medicinal chemistry methods aimed towards the understanding of estrogen receptors (ERs) and breast cancer. Breast cancer is the second most common cancer and the second leading cause of cancer fatalities in women in the United States. These devastating statistics are partially attributed to unreliable diagnosis, reoccurrence and drug resistance. Approximately 70% of these cancers express ERs, making them a relevant target for the development of new therapeutics and investigation into the mechanism of this disorder. A major portion of this project focuses on the design and synthesis of compound libraries directed towards ERs that will utilize natural products as their starting point. From a family of compounds called the flavonoids that contain estrogenic (glycinol) and anti-estrogenic (glyceollins) members, we devised new structures that are meant to exploit key binding interactions within the ER. Studies leading to these target compound libraries include the design and synthesis of 'model' compound libraries meant to mimic the target structure's corresponding pharmacophores. By developing the model libraries we were able to explore synthetic methods that could be used for the synthesis of the targets. Additionally, one set of these libraries was also used to obtain initial biological data to develop structure-activity relationships that, in turn, contributed to final target selection. To further support our target design we studied our compound libraries (target and model) via ER docking paradigms derived from protein database starting points. To properly conduct these experiments we first determined an appropriate protein docking model for our natural product system. This docking model was designed in such a way as to best describe the biological profile of known agents and a group of our natural products. Using this protein docking model, we examined our compound libraries allowing for a more direct comparison between the two systems. Additional studies were directed toward the androgen receptor (AR) and prostate cancer. The rationale for these studies includes implications that androgens and ARs are involved in breast cancer. Furthermore, the glyceollin group from the flavonoid family has shown anti-androgen potential. Similar to the ER experiments, an X-ray derived protein docking model for the AR was devised to describe the biological profile of known agents and some of the glyceollins. This docking model was then used to study all the compound libraries. A final project was an investigation into the role of retinoic acid receptors (RARs) in breast cancer. Preliminary research implies that RARs may play a role in breast cancer drug resistance. In order to help address this hypothesis, we first synthesized a known agent to probe the RAR subtype involved in breast cancer, RARα. Secondly, we suggested other possible agents that may work as scaffolds for designing new, more specific probes. We devised a new synthetic route to these agents that ultimately led to higher yields, lower cost and decreased labor compared to that for the original standard. In this dissertation all of these topics are discussed in greater detail. Each chapter focuses on a different project and provides a synopsis of the methods utilized. Similarly, results from the methods and conclusions are given for each project including comments on their future directions.

Most drugs are analogue drugs. There are no general rules how a new drug can be discovered, nevertheless, there are some observations which help to find a new drug, and also an individual story of a drug discovery can initiate and help new discoveries. Volume III is a continuation of the successful book series with new examples of established and recently introduced drugs. The major part of the book is written by key inventors either as a case study or a study of an analogue class. With its wide range across a variety of therapeutic fields and chemical classes, this is of interest to virtually every researcher in drug discovery and pharmaceutical chemistry, and -- together with the previous volumes -- constitutes the first systematic approach to drug analogue development.

Eukaryotic initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF), promotes protein synthesis by charging translation initiation factor 2 (eIF2) with GTP. Stress-induced phosphorylation of eIF2 on its α-subunit [eIF2(αP)] inhibits this reaction triggering a protective Integrated Stress Response (ISR). A DNA-encoded chemical library (DEL) screen for modulators of eIF2B, led to the identification of a chemical series that inactivates eIF2B, stimulating the ISR. Cryo-EM of compound-bound eIF2B revealed a conformational switch to the inactive state engaged by eIF2(αP). In cells, compound activity was sensitive to eIF2’s phosphorylation state and to a competing eIF2B ligand (ISRIB) that activates the GEF allosterically. These findings mark the discovery of a first-in-class drug-like allosteric inhibitor of eIF2B, an ISR activator (ISRAC), paving the way to explore the therapeutic potential of eIF2B-directed ISR activation.

This chapter contains sections titled: List of Abbreviations Introduction Tamoxifen Raloxifene Summary References