Doctor of Philosophy (Ph.D.)
Degree Granting Department
Ernst Schönbrunn, Ph.D.
Yu Chen, Ph.D.
Robert Deschenes, Ph.D.
Gloria Ferreira, Ph.D.
Jiandong Chen, Ph.D.
Andreas Seyfang, Ph.D.
Jun Qi, Ph.D.
X-ray crystallography, Drug discovery, Kinase inhibitor, Structural biology, TAF1, BRD9, BRD7, TRIM28, Dual BRD-kinase inhibitor, BET
The epigenetic “reader” modules bromodomains (BRDs) exert their diverse cellular functions through the recognition of acetylated lysines on histones and other proteins. Small molecule inhibitors of bromodomains have emerged as a promising therapeutic strategy to treat atherosclerotic cardiovascular diseases and cancers. Therefore, a large number of small molecule bromodomain inhibitors have been developed in the last decade, some of which are currently being assessed in the clinic. However, the success of bromodomain inhibitors is currently limited to the bromodomain and extra-terminal domain (BET) subfamily.
To address these, bromodomains outside the BET subfamily (non-BETs) such as TAF1, BRD7/9, TRIM28, and BRD8 were studied in detail. The first dual non-BET BRD-kinase inhibitors were discovered for TAF1 (chapter 2) and BRD7/9 (chapter 3), which includes the dual TAF1-ATR inhibitor AZD6738, and dual BRD7/9-kinase inhibitors TG003, sunitinib, and PF477736. Structural and biochemical studies with TAF1 showed that inhibitor binding to the tandem bromodomain of TAF1 induces large conformational changes, and bromodomain inhibition of TAF1 invokes p53-mediated DNA damage response. Moreover, a comprehensive characterization of diverse BRD7/9 inhibitors, along with the newly discovered dual BRD7/9-kinase inhibitors, provides a new structural framework for the development of BRD7/9 inhibitors with improved selectivity or additional polypharmacologic properties.
To develop a selective and effective BET bromodomain inhibitor, structure-activity relationship studies, and biophysical characterization of various dual BET-kinase inhibitors and bivalent inhibitors were conducted. The dual BET-JAK2 inhibitor lead compounds developed from the studies (chapter 4 part I) will serve as potential drug candidates for testing in preclinical disease models. Moreover, studies with a set of PLK1/ERK5/LRRK2 inhibitors against the BET BRDs (chapter 4 part II) provide a structural basis for developing a dual BET-PLK1/ERK5 inhibitor for synergistic pharmacological benefits. Finally, studies with the bivalent inhibitors (chapter 5) showed that homomeric bivalent inhibitors of BRD4 and BRDT induce the dimerization of BRDs, and the potent bivalent inhibitor NC-III-49-1 engages the tandem BRD of BRDT in an intramolecular fashion. Combined, these studies provide valuable chemical tools that can be utilized to progress towards the development of selective and effective BET bromodomain inhibitors as potential therapeutic candidates.
Scholar Commons Citation
Karim, Md Rezaul, "Discovery and Characterization of Small Molecule Inhibitors of Bromodomains" (2020). Graduate Theses and Dissertations.