The field of proteolysis targeting chimeras (PROTACs) has been rapidly expanding over the last twenty years due to its viability as an anticancer treatment approach. PROTAC development includes the design of a bifunctional molecule, including an E3 ligase ligand, target protein ligand, and “linker” region binding the two ligands together. Through these PROTACs, targeted protein degradation has been achieved for multiple proteins in a variety of cancer types. The PROTAC forms a ternary complex with the E3 ligase and target protein, with the E3 ligase ubiquitinating the target protein, leading to subsequent degradation by the 26S proteasome in the cell, removing the target protein altogether. Currently, our lab is focusing efforts towards targeted CDK9 degradation in treatment of leukemia. The CDK9 pathway plays a significant role in gene transcription and mRNA maturation whose dysregulation is associated with leukemia development. Both CDK9 inhibition and degradation have been established as viable options for leukemia treatment, with CDK9 degradation holding an immense amount of promise as a therapeutic route due to the long-lasting anti-proliferative effects seen in cancer cells. Utilizing the cereblon E3 ligase as the desired ubiquitinating machinery for CDK9, numerous PROTAC analogues have been created utilizing either 4-hydroxythalidomide or pomalidomide as the E3 ligase ligand. The distance between the E3 ligase ligand and CDK9 ligand were varied by placing a variety of linker types and lengths between the E3 ligase ligand and CDK9 ligand, allowing for determination of optimal linker length and composition to allow for CDK9 degradation. The synthesis of these CDK9 PROTAC analogues, as well as the biological data for this compound class, will be discussed.

Design and synthesis of novel CDK9-specific PROTACs for the treatment of leukemia

2019 Fall National Meeting

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