Bfl-1-IN-5 is a covalent and selective Bfl-1 inhibitor with an IC50 of 22 nM. Bfl-1-IN-5 shows selectivity for Bfl-1 over Bcl-xl, Bcl-2 and Mcl-1. Bfl-1-IN-5 induces caspase-3/7 activation, reduces the viability of Bfl-1-expressing lymphoma cells in combination with an Mcl-1 inhibitor, and binds covalently to intracellular Bfl-1. Bfl-1-IN-5 can be used for lymphoma research [1].
In Vitro, Bfl-1-IN-5 ((R,R,S)-26) (100 μM; 120 min) inhibits Bfl-1-Bim interaction in a biochemical TR-FRET assay with an IC50 of 0.022 μM[1]. Bfl-1-IN-5 is selective for Bfl-1 over Bcl-xl, Bcl-2, and Mcl-1 with IC50 values greater than 30, 30, and 100 μM, respectively[1]. Bfl-1-IN-5 (10 μM; 5 h) engages endogenous Bfl-1 covalently in SU-DHL-1 cells, demonstrating cellular target engagement[1]. Bfl-1-IN-5 shows low intrinsic clearance in human liver microsomes and human hepatocytes, with substantially higher clearance in mouse hepatocytes[1]. Bfl-1-IN-5 (0.3 nM-10 μM; 6 h) activates caspase-3/7 in SU-DHL-1 cells with an EC50 of 0.37 μM when combined with Mcl-1 inhibitor AZD-5991 [1]. Bfl-1-IN-5 (0.3 nM-10 μM; 24 h) reduces viability of SU-DHL-1 cells with an EC50 of 1.3 μM when combined with AZD-5991[1]. Bfl-1-IN-5 (0.3 nM-10 μM; 24 h) does not reduce viability of Bfl-1-null Karpas-422 cells at concentrations up to 10 μM, consistent with Bfl-1-dependent activity[1].
References:
[1]. Lucas SCC, et al. Structure-Based Optimization of a Series of Covalent, Cell Active Bfl-1 Inhibitors. Journal of medicinal chemistry. 2024 Sep 26;67(18):16455-16479.
In Vitro, Bfl-1-IN-5 ((R,R,S)-26) (100 μM; 120 min) inhibits Bfl-1-Bim interaction in a biochemical TR-FRET assay with an IC50 of 0.022 μM[1]. Bfl-1-IN-5 is selective for Bfl-1 over Bcl-xl, Bcl-2, and Mcl-1 with IC50 values greater than 30, 30, and 100 μM, respectively[1]. Bfl-1-IN-5 (10 μM; 5 h) engages endogenous Bfl-1 covalently in SU-DHL-1 cells, demonstrating cellular target engagement[1]. Bfl-1-IN-5 shows low intrinsic clearance in human liver microsomes and human hepatocytes, with substantially higher clearance in mouse hepatocytes[1]. Bfl-1-IN-5 (0.3 nM-10 μM; 6 h) activates caspase-3/7 in SU-DHL-1 cells with an EC50 of 0.37 μM when combined with Mcl-1 inhibitor AZD-5991 [1]. Bfl-1-IN-5 (0.3 nM-10 μM; 24 h) reduces viability of SU-DHL-1 cells with an EC50 of 1.3 μM when combined with AZD-5991[1]. Bfl-1-IN-5 (0.3 nM-10 μM; 24 h) does not reduce viability of Bfl-1-null Karpas-422 cells at concentrations up to 10 μM, consistent with Bfl-1-dependent activity[1].
References:
[1]. Lucas SCC, et al. Structure-Based Optimization of a Series of Covalent, Cell Active Bfl-1 Inhibitors. Journal of medicinal chemistry. 2024 Sep 26;67(18):16455-16479.