UC San Diego

Atropisomerism is a form of conformational chirality that occurs when there is hindered rotation about a bond. Class-1 atropisomers are quite prevalent in modern drug discovery with ~1/3 of recent FDA-approved small molecules (and ~80% of FDA-approved kinase inhibitors) possessing at least one potentially atropisomeric axis. Obtaining selective small molecule kinase inhibitors has proved to be very challenging in drug discovery, and is crucial as off-target inhibition can lead to severe side effects in patients that limit drug safety and efficacy. Previously, the Gustafson lab hypothesized that different proteins prefer to bind to different conformations of the same molecule, and that preorganizing the molecule in the therapeutic target’s preferred binding conformation will increase target selectivity by precluding binding to proteins that prefer other conformations. Chapter 1 overviews atropisomerism and its prevalence in drug discovery, including previewing heterobiaryl systems such as pyrrolopyrimidines (PPYs) and pyridones, which my dissertation research has primarily focused on. My Ph.D. research begins in chapter 2, where we leveraged conformational control about a prospective atropisomeric axis to obtain a highly selective and potent inhibitor of BTK. Along the way, we hypothesized that we could apply our strategy of conformational control about a prospective atropisomeric axis to increase target selectivity in other scaffolds prevalent throughout medicinal chemistry. This led to my work in chapter 3, where we introduced stable atropisomerism into analogs of the promiscuous FDA-approved kinase inhibitor, ripretinib, resulting in a highly potent and selective inhibitor of mutant c-KIT in gastrointestinal stromal tumors (GIST). Moreover, chapter 4 explores the use of atropisomerically stable ripretinib analogs with a ‘covalent tag’ to identify new therapeutic protein targets in collaboration with the Backus group at UCLA. In conclusion, we have shown that leveraging stable atropisomerism or conformational control about a prospective atropisomeric axis has led to the development of highly selective and potent small molecules in diseases such as cancer, and thus should be utilized as a strategy to design targeted therapeutics in drug discovery.