brd2

PROTAC BRD2 BRD4 degrader-1 (compound 15) is a potent, selective degrader of BET proteins BRD4 and BRD2, achieving rapid, reversible, and unexpectedly selective elimination compared to BRD3. It effectively suppresses solid tumors with minimal cytotoxic effects and comprises a BET inhibitor, a connecting linker, and thalidomide as the ligand for cereblon (CRBN) cullin 4A[1].

ARV-771 is a potent BET degrader based on PROTAC technology, with Kds of 34 nM for BRD2(1), 4.7 nM for BRD2(2), 8.3 nM for BRD3(1), 7.6 nM for BRD3(2), 9.6 nM for BRD4(1), and 7.6 nM for BRD4(2), respectively[1].

BETd-260, a PROTAC linked by a Cereblon ligand and a BET ligand, has an inhibitory effect on BRD4 protein in leukemic cell lines.

WWL0245 is a potent and selective BRD4-targeting PROTAC that exhibits sub-nanomolar degradation efficiency (DC50 < 1 nM) for BRD4 over BRD2 3 and PLK1 (DC50 > 1 μM). It demonstrates pronounced selective cytotoxicity in BETi-sensitive cancer cell lines, particularly in AR-positive prostate cancer lines, making it a promising candidate for research in AR-positive prostate cancer and a valuable tool for the investigation of BRD4's biological function [1].

HJB97 is used for the design of potential PROTAC BET degrader. It also has antitumor activity. HJB97 is a high-affinity inhibitor of BET (Kis: 0.9 nM (BRD2 BD1), 0.27 nM (BRD2 BD2), 0.18 nM (BRD3 BD1), 0.21 nM (BRD3 BD2), 0.5 nM (BRD4 BD1), 1.0 nM (BRD4 BD2), respectively).

Thalidomide-NH-C4-NH2 TFA (compound 29c) is a conjugate composed of an E3 ligase ligand-linker that integrates a Thalidomide-based cereblon ligand and a linker moiety. This compound is used as a component in PROTAC BRD2 BRD4 degrader-1, a highly potent and selective degrader targeting BET proteins BRD4 and BRD2[1].

dBRD4-BD1 is a selective BRD4 bromodomain inhibitor. dBRD4-BD1 can selectively degrade BRD4 (DC50 = 280 nM). Notably, dBRD4-BD1 upregulates BRD2/3, a result not observed with degraders using pan-BET ligands. Designing BRD4 selectivity up front enables analysis of BRD4 biology without wider BET-inhibition and simplifies designing BRD4-selective heterobifunctional molecules, such as degraders with new E3 recruiting ligands or for additional probes beyond degraders.

KB02-JQ1 is a potent and specific proteolysis targeting chimera (PROTAC) that specifically degrades BRD4, acting as a molecular glue. It does not degrade BRD2 or BRD3. The mechanism of action involves covalent modification of the E3 ligase DCAF16, thereby promoting BRD4 degradation. Importantly, KB02-JQ1 demonstrates enhanced stability and durability in facilitating protein degradation within biological systems. The compound forms a complex with the ubiquitin E3 ligase ligand KB02 through a linker, resulting in the formation of KB02-JQ1[1].

BET-IN-6, a ligand with potent and high affinity for inhibiting BRD2/BRD4, plays a crucial role in the synthesis of PROTAC BRD2/BRD4 degrader-1 [1], targeting the protein BRD2/4.

OARV-771, a VHL-based BET degrader (PROTAC) featuring enhanced cell permeability, demonstrates DC50 values of 6 nM for Brd4, 1 nM for Brd2, and 4 nM for Brd3, respectively [1].

SIM1 is a potent and selective trivalent PROTAC®Degrader based on BET bromodomain inhibitors linked to a Von Hippel Lindau (VHL) ligand via branched linkers. SIM1 degrades all BET family proteins with a preference for BRD2 (DC50values = 0.7 nM, 1.1 nM and 3.3 nM for BRD4, BRD2 and BRD3, respectively). SIM1 degrades BRD2 more significantly and rapidly than BRD3 and BRD4, and degrades BET proteins with a higher potency than a bivalent degrader. SIM1 also decreases protein levels for Myc and HMOX1 and induces apoptosis in prostate cancer cells.

BRD4 degrader AT1 is a highly selective Brd4 degrader based on PROTAC technology, with a Kd of 44 nM for Brd4BD2 in cells.

MZ 1 is a BRD4 protein degrader based on PROTAC technology.