Abstract
Phthalimide conjugates induce destabilization of target proteins such as BRD4 in vitro and in vivo.
Major finding: Phthalimide conjugates induce destabilization of target proteins such as BRD4 in vitro and in vivo.
Concept: Phthalimide conjugation triggers cereblon-mediated proteasomal degradation of target proteins.
Impact: This chemical strategy may represent a broad approach to develop new cancer therapeutics.
Despite the clinical efficacy of compounds such as fulvestrant that induce ligand-dependent destabilization of target proteins, the development of additional target-degrading compounds has remained limited due to ligand requirements, lack of specificity, and low cellular potency. Recent work has shown that phthalimide-based drugs target cereblon (CRBN), a member of the cullin–RING ubiquitin ligase complex, to promote proteasomal degradation of specific transcription factors. To test the broader applicability of this concept, Winter, Buckley, and colleagues generated a bifunctional phthalimide-conjugated version of JQ1, a BET bromodomain inhibitor that displaces the transcriptional coactivator bromodomain-containing 4 (BRD4) from chromatin, resulting in transcriptional downregulation of MYC and induction of antiproliferative responses in leukemia cells. Chemical substitutions at the carboxyl group of JQ1 and the aryl ring of thalidomide yielded dBET1, which retained specific BRD4 binding, bridged BRD4 and CRBN, and rapidly destabilized BRD4 protein in a dose-dependent manner in acute myeloid leukemia (AML) cells. Mechanistically, dBET1-mediated BRD4 protein destabilization was dependent on the proteasome and BRD4–CRBN engagement. Functionally, dBET1 resulted in selective proteomic changes in AML cells, including downregulation of MYC and PIM1, similar to the effects of JQ1 treatment, as well as a marked reduction in the levels of other BET family members, reinforcing compound specificity. Treatment with dBET1 induced a superior apoptotic response compared with JQ1 in leukemia cells and primary human leukemic blasts in vitro, and attenuated proliferation and leukemic progression in vivo without toxicity, underscoring the potential clinical utility of this approach. In addition, this strategy was applied to design phthalimide-conjugated ligands that stimulated CRBN-dependent degradation of a second target, the cytosolic protein FK506-binding protein 1A (also known as FKBP12). Together, this work highlights a chemical approach for inducing selective protein degradation that has the potential for broader application in the development of new anticancer therapies.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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