L134 is a BRD4 PROTAC degrader with a DC50 of 7.36 nM. L134 induces BRD4 protein degradation without inhibiting BRD4 gene expression, and recruits the E3 ubiquitin ligase DCAF11 to mediate this process, which can be blocked by proteasome inhibitors (MG132, PS341 ) and E1 ubiquitin ligase inhibitors (PYR41, MLN4924 ). L134 inhibits cancer cell migration, promotes cancer cell apoptosis and exerts antiproliferative activity. L134 can be used in studies related to triple-negative breast cancer [1]. (Pink: BRD4 ligand; Blue: Cereblon ligand; Black: linker ).
In Vitro, L134 (10 nM-1000 nM; 12 h) potently degrades BD1, a domain of BRD4, in HEK293T cells stably expressing the BD1 reporter gene, with significant degradation effects observable at concentrations as low as 10 nM[1]. L134 (10 nM-1000 nM; 1 h-24 h) efficiently degrades BRD4 in MDA-MB-231 cells via the ubiquitin-proteasome pathway, with a DC50 of 7.36 nM. A significant degradation effect is observed within 1 h of treatment with 1 μM[1]. L134 (1 μM; 12 h)-mediated degradation of BRD4 in HEK293T reporter cells depends on DCAF11, as it promotes the formation of a complex between BRD4 and the E3 ubiquitin ligase DCAF11[1]. L134 (48 h) inhibits the proliferation of various breast cancer cell lines, with the strongest inhibitory activity against MDA-MB-468 cells (IC50 = 0.02 μM) and MDA-MB-231 cells (IC50 = 0.07 μM)[1]. L134 (12 h-24 h) inhibits the migration of MDA-MB-231 breast cancer cells[1]. L134 (0.5 μM-1.0 μM; 48 h) inhibits the migration of MDA-MB-231 breast cancer cells in a dose-dependent manner[1]. L134 induces apoptosis in MDA-MB-231 breast cancer cells via its intact PROTAC structure, which is confirmed by increased levels of cleaved PARP and cleaved Caspase-7[1].
References:
[1]. Zhao M, et al. Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair. Journal of medicinal chemistry. 2024 Nov 14;67(21):19428-19447.
In Vitro, L134 (10 nM-1000 nM; 12 h) potently degrades BD1, a domain of BRD4, in HEK293T cells stably expressing the BD1 reporter gene, with significant degradation effects observable at concentrations as low as 10 nM[1]. L134 (10 nM-1000 nM; 1 h-24 h) efficiently degrades BRD4 in MDA-MB-231 cells via the ubiquitin-proteasome pathway, with a DC50 of 7.36 nM. A significant degradation effect is observed within 1 h of treatment with 1 μM[1]. L134 (1 μM; 12 h)-mediated degradation of BRD4 in HEK293T reporter cells depends on DCAF11, as it promotes the formation of a complex between BRD4 and the E3 ubiquitin ligase DCAF11[1]. L134 (48 h) inhibits the proliferation of various breast cancer cell lines, with the strongest inhibitory activity against MDA-MB-468 cells (IC50 = 0.02 μM) and MDA-MB-231 cells (IC50 = 0.07 μM)[1]. L134 (12 h-24 h) inhibits the migration of MDA-MB-231 breast cancer cells[1]. L134 (0.5 μM-1.0 μM; 48 h) inhibits the migration of MDA-MB-231 breast cancer cells in a dose-dependent manner[1]. L134 induces apoptosis in MDA-MB-231 breast cancer cells via its intact PROTAC structure, which is confirmed by increased levels of cleaved PARP and cleaved Caspase-7[1].
References:
[1]. Zhao M, et al. Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair. Journal of medicinal chemistry. 2024 Nov 14;67(21):19428-19447.