RAJQ14

RAJQ14 is a BRD4 PROTAC degrader that binds to 19S proteasome cap subunits RPN1, RPN10, RPN13, and USP14, recruiting target proteins to the proteasome for degradation in a ubiquitin-independent but proteasome-dependent manner. This compound is applicable in cancer research.

RAJQ14 (10 μM) selectively binds the bromodomains of BRD2, BRD3, and BRD4, enhancing their thermal stability. In living HEK293T cells, RAJQ14 (10 μM; 2 h) can simultaneously bind RPN13 and BRD4. At concentrations of 0.1-2.5 μM, RAJQ14 induces dose- and time-dependent degradation of BRD4 within HEK293T cells over a period of 2-24 hours. Specifically, at 1 μM for 6 hours, RAJQ14 results in selective degradation of BRD2, BRD3, and BRD4 in HEK293T cells without off-target degradation of other bromodomain proteins. Additionally, RAJQ14 (0.1-2.5 μM; 24 h) can trigger CRBN-independent BRD4 degradation in CRBN-knockout HEK293T cells. In HCT116 cells, treatment with RAJQ14 (1-100 μM; overnight) allows binding to multiple 19S proteasome cap subunits (including RPN1, RPN10, RPN13, and USP14) as well as BET proteins (BRD2, BRD3, BRD4), independently of RPN13 expression. Furthermore, in RPN13-knockout HCT116 cells, RAJQ14 (0.1-2.5 μM; 24 h) promotes RPN13-independent degradation of BRD4, potentially through binding to other 19S proteasome cap subunits. In T47D-shRPN1-Dox cells, RAJQ14 at similar concentrations induces BRD4 degradation not entirely dependent on RPN1, as compensatory upregulation of RPN13 and RPN11 maintains the degrader's activity. Lastly, RAJQ14 (2.5 μM; 6 h) induces BRD4 degradation in HEK293T cells via a ubiquitination-independent mechanism, as no ubiquitination of BRD4 is detected during this process.