Abstract IA31: Phthalimide conjugation as a strategy for targeted protein degradation

Ligand-induced target protein destabilization is an efficacious therapeutic strategy in cancer, but discovery in this field has historically been serendipitous given the lack of rational design principles. Building on the molecular logic of immunomodulatory drugs (“IMiDs”), we innovated a facile chemical solution for targeted protein degradation using bifunctional small molecules capable of recruiting the E3 ligase cereblon (CRBN). These bifunctional molecules induce immediate, and complete proteasomal degradation of their target proteins and thus represent a novel class of small molecule therapeutics with an entirely uncharted and unique molecular pharmacology.

Focusing our initial efforts on degraders of the BET family of proteins, we observed that they exhibit superior efficacy than BET inhibitors through unknown mechanisms. In order to dissect and mechanistically explain that differential molecular pharmacology, we used optimized small-molecule degraders and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in global control of transcriptional pause-release. Targeted BET degradation nucleates a collapse in the transcriptional core regulatory circuitry and thus enabled us to exploit transcriptional addictions in T-Cell acute lymphoblastic leukemia (T-ALL) that were intractable using competitive BET bromodomain inhibitors.

Citation Format: Georg E. Winter, Dennis L. Buckley, James E. Bradner. Phthalimide conjugation as a strategy for targeted protein degradation. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA31.