Chemical Tools to Study Bromodomains in Cancer
Remillard, David Ian
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CitationRemillard, David Ian. 2018. Chemical Tools to Study Bromodomains in Cancer. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractFactors that regulate chromatin structure collaborate with transcription factors to establish and maintain cellular expression programs in both normal physiology and disease. Small molecule approaches offer a unique opportunity for direct influence on the endogenous machinery driving these processes, as previously exemplified by inhibitors of the BET coactivator family’s acetyl-lysine reader domains (bromodomains). The current work describes the development and application of chemical tools to study bromodomains containing proteins outside of this family.
Approaches to modulate ligand-bromodomain binding are discussed in Chapter I, which details structure activity relationships toward selective binders of the TAF1. This dual-bromodomain containing initiation factor is of interest for its annotated roles in gene control as the largest member of TFIID, the pioneer initiation factor in eukaryotic transcription. From a non-selective multi-target binder, structure-based design strategies are applied to guide potency and selectivity from a kinase inhibitor derived chemical scaffold.
The application of established but ineffectual bromodomain ligands for chemical degradation strategies is discussed in Chapter II, which describes the development of a selective chemical degrader for BRD9 (dBRD9) through iterative design and evaluation. As a member of the frequently BAF chromatin remodeling complex, BRD9 has been annotated to play a supportive role in acute myeloid leukemia. The latter half of this chapter thus discusses application of dBRD9 to corroborate and exploit this dependency, and provides evidence for an on-target mechanism of action through complementary chemical and genetic approaches.
The BAF complex is frequently mutated in human cancer, resulting in novel dependencies on complex members that are required for residual complexes, or that support hyperactive complex assemblies. We describe in Chapter III application of our BRD9 degradation strategy to synovial sarcoma, an aggressive early onset cancer driven by activating SS18-SSX fusion oncogene within BAF. In collaboration with the Vakoc and Armstrong laboratories, we define BRD9 inactivation as a novel vulnerability in this disease, characterize the response to acute BRD9 loss, and demonstrate efficacy for BRD9 degradation in both culture and animal models of this disease.
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