BRD4

5nM(DC₅₀,5hoursoftreatment)

Cereblon

ZXH-3-26 is a PROTAC connected by ligands for Cereblon and BRD4 with a DC50/5h of 5 nM. The DC50/5h refers to half-maximal degradation after 5 hours of treatment of ~ 5 nM[1].

ZXH-3-26 represents the first small molecule to allow pharmacologic targeting of BRD4 without significant inhibition or degradation of BRD2/3[1]. ZXH-3-26 shows activity exclusively on the first bromodomain of BRD4, and spares degradation of BRD2/3 at concentrations 10 μM. Immunoblot analysis confirms that ZXH-3-26 degrades endogenous BRD4 with comparable efficacy compared to the best pan-BET degrader dBET6, while being inactive on BRD2/3[1]. ZXH-3-26 engages CRBN in a conformation distinct[1].

[1]. Nowak RP, et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat Chem Biol. 2018 Jul;14(7):706-714.