PDBsum entry 4zc9

Signaling protein/inhibitor

PDB id: 4zc9

Contents

Protein chain

127 a.a.

Ligands

4MW

Waters ×162

References listed in PDB file

Key reference

• Title: Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation.
• Authors: G.E.Winter, D.L.Buckley, J.Paulk, J.M.Roberts, A.Souza, S.Dhe-Paganon, J.E.Bradner.
• Ref.: Science, 2015, 348, 1376-1381. [DOI no: 10.1126/science.aab1433]
• PubMed id: 25999370

Abstract

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 to a phthalimide moiety 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.