Phthalimide conjugation as a strategy for in vivo target protein degradation
Menée in vitro et in vivo, cette étude met en évidence l'efficacité d'une stratégie chimique à base de conjugués entre une molécule active (JQ1) et un dérivé de la thalidomide (phthalimide) permettant la dégradation sélective de protéines notoirement difficiles à cibler, par exemple la protéine BRD4 impliquée dans la croissance des cellules leucémiques
The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains with phthalimide-conjugates to hijack the Cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective Cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein, FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.
Science 2015