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Design and synthesis of novel bispecific molecules for inducing BRD4 protein degradation
Proteolysis targeting chimeras(PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. Recently, some heterobifunctional small molecule bromodomain-containing protein 4(BRD4) degraders based on the concept of PROTACs were designed to induce the degradation of BRD4 protein. Herein, we synthesized a new class of PROTAC BRD4 degraders. One of the most promising compound 22f exhibited robust potency of BRD4 inhibition with IC50 value of (9.4¡À0.6) nmol/L. Furthermore, compound 22f potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC50 value of (27.6¡À1.6) nmol/L and capable of inducing degradation of BRD4 protein at 0.5?1.0 mumol/L in the RS4;11 cells. These data establish that compound 22f is a potent and efficacious BRD4 degrader.
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Reference£º
Benzofuran – Wikipedia,
Benzofuran | C8H2561O – PubChem