TrimTAC1 is a TRIM21 -based PROTAC degrader targeting BRD4, with a DC50 of 0.649 nM. TrimTAC1 selectively degrades multimeric proteins, including those localized in biomolecular condensates, while exerting no effect on monomeric proteins in the dilute phase. This degradation effect can be blocked by Bortezomib or TAK-243. TrimTAC1 can be used in research related to pancreatic cancer and autoimmune diseases [1] [2]. (Pink: BRD4 ligand; Blue: TRIM21 ligand; Black: linker ).
In Vitro, TrimTAC1 (24 h) potently degrades BRD4 in PANC-1 cells, with a DC50 of 0.649 nM and a maximum degradation rate of 71%[1]. TrimTAC1 (3 days) inhibits the proliferation of PANC-1 cells, with a GI50 value of 0.103 μM[1]. TrimTAC1 forms a highly stable, low-energy conformation with BRD4. The spatial orientation of this conformation facilitates efficient ubiquitination, which correlates with its experimentally observed high activity in degrading BRD4 within the TRIM21-TrimTAC1-BRD4 ternary complex[1]. TrimTAC1 exhibits high thermodynamic stability and shows strong positive cooperative binding between TRIM21 and BRD4. The interactions in the TRIM21-TrimTAC1-BRD4 ternary complex are mediated by key hydrophobic and electrostatic residues[1]. TrimTAC1 exhibits physicochemical properties consistent with the favorable membrane permeability and solubility required for targeted protein degrader applications (log P = 4.7, log D7.4 = 4.9)[1]. TrimTAC1 (0-20 μM; 12 h) exhibits no molecular glue degrader activity against nucleoporins in IFNγ-pretreated A549 cells[2]. TrimTAC1 (4 h) does not degrade monomeric mEGFP-BRD4BD2 in A549 cells expressing TRIM21D355A[2]. TrimTAC1 (2 μM; 4 h) efficiently degrades condensate-forming NUP98FG-mEGFP-BRD4BD2 in A549 cells expressing TRIM21D355A via a proteasome- and ubiquitination-dependent mechanism[2]. TrimTAC1 (2 μM; 4 h) selectively degrades mEGFP fusion proteins that form condensates (PML, coilin, NPM1) in A549 cells expressing TRIM21D355A, but does not degrade non-condensate-forming mEGFP fusion proteins (CDK4, BTK)[2]. TrimTAC1 (2 μM; 6 h) selectively degrades DNA-induced BRD4BD2-mEGFP-cGAS condensates in HaCaT cells expressing TRIM21D355A, without affecting soluble BRD4BD2-mEGFP-cGAS[2].
References:
[1]. Zhang L, et al. TRIM21-Driven Degradation of BRD4: Development of Heterobifunctional Degraders and Investigation of Recruitment and Selectivity Mechanisms. Journal of chemical information and modeling. 2025 Jul 28;65(14):7584-7604.
[2]. Lu P, et al. Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders. Cell. 2024 Dec 12;187(25):7126-7142.e20.
In Vitro, TrimTAC1 (24 h) potently degrades BRD4 in PANC-1 cells, with a DC50 of 0.649 nM and a maximum degradation rate of 71%[1]. TrimTAC1 (3 days) inhibits the proliferation of PANC-1 cells, with a GI50 value of 0.103 μM[1]. TrimTAC1 forms a highly stable, low-energy conformation with BRD4. The spatial orientation of this conformation facilitates efficient ubiquitination, which correlates with its experimentally observed high activity in degrading BRD4 within the TRIM21-TrimTAC1-BRD4 ternary complex[1]. TrimTAC1 exhibits high thermodynamic stability and shows strong positive cooperative binding between TRIM21 and BRD4. The interactions in the TRIM21-TrimTAC1-BRD4 ternary complex are mediated by key hydrophobic and electrostatic residues[1]. TrimTAC1 exhibits physicochemical properties consistent with the favorable membrane permeability and solubility required for targeted protein degrader applications (log P = 4.7, log D7.4 = 4.9)[1]. TrimTAC1 (0-20 μM; 12 h) exhibits no molecular glue degrader activity against nucleoporins in IFNγ-pretreated A549 cells[2]. TrimTAC1 (4 h) does not degrade monomeric mEGFP-BRD4BD2 in A549 cells expressing TRIM21D355A[2]. TrimTAC1 (2 μM; 4 h) efficiently degrades condensate-forming NUP98FG-mEGFP-BRD4BD2 in A549 cells expressing TRIM21D355A via a proteasome- and ubiquitination-dependent mechanism[2]. TrimTAC1 (2 μM; 4 h) selectively degrades mEGFP fusion proteins that form condensates (PML, coilin, NPM1) in A549 cells expressing TRIM21D355A, but does not degrade non-condensate-forming mEGFP fusion proteins (CDK4, BTK)[2]. TrimTAC1 (2 μM; 6 h) selectively degrades DNA-induced BRD4BD2-mEGFP-cGAS condensates in HaCaT cells expressing TRIM21D355A, without affecting soluble BRD4BD2-mEGFP-cGAS[2].
References:
[1]. Zhang L, et al. TRIM21-Driven Degradation of BRD4: Development of Heterobifunctional Degraders and Investigation of Recruitment and Selectivity Mechanisms. Journal of chemical information and modeling. 2025 Jul 28;65(14):7584-7604.
[2]. Lu P, et al. Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders. Cell. 2024 Dec 12;187(25):7126-7142.e20.