OH14 is a cellular FLICE-like inhibitory protein ( cFLIP) inhibitor and TNF-related apoptosis-inducing ligand ( TRAIL ) sensitizer. OH14 selectively binds to the DED1 pocket of cFLIP, disrupting its recruitment to the TRAIL-death inducing signalling complex without affecting procaspase-8 recruitment to FADD, allowing procaspase-8 activation. OH14 promotes TRAIL-mediated apoptosis and impairs cell viability in breast cancer systems when combined with TRAIL. OH14 can be used for the research of breast cancer [1].
In Vitro, OH14 (75-100 μM; 1 h) sensitizes MCF-7 breast cancer cells and HeLa cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in a dose-dependent manner, as measured by increased cleaved caspase 3/7 activity and Annexin V staining, respectively[1]. OH14 (100 μM; 1 h) requires the R38 residue in cFLIP to sensitize HeLa cells to TRAIL-induced apoptosis, while overexpression of wild-type, H7A, or K18I/R45A mutant cFLIP does not impair this sensitizing activity[1]. OH14 (100 μM; 1 h) significantly sensitizes MCF-7, BT474, and MDA-MB-231 breast cancer cell lines to TRAIL-induced cell death, with variable effects across other breast cancer subtypes[1]. OH14 (100 μM; 1 h) disrupts TRAIL-mediated recruitment of cFLIP to FADD in HeLa cells, as measured by loss of FRET signal between cFLIP-YFP and FADD-CFP[1]. OH14 (100 μM; 1 h) specifically disrupts TRAIL-mediated recruitment of cFLIP to the FADD complex in MCF-7 cells, while allowing procaspase-8 cleavage and activation[1]. OH14 (10 μM; 10 days) sensitizes MCF-7 breast cancer cells to TRAIL-induced reduction in colony formation, without affecting colony growth when administered alone[1]. OH14 (10 μM; 24 h) is non-toxic to HEK293 non-tumorigenic human embryonic kidney cells, either alone or in combination with TRAIL[1].
References:
[1]. Giancotti G, et al. The Discovery of Small Molecule Inhibitors of cFLIP that Sensitise Tumour Cells to TRAIL[J]. bioRxiv, 2024: 2024.04. 22.590574.
In Vitro, OH14 (75-100 μM; 1 h) sensitizes MCF-7 breast cancer cells and HeLa cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in a dose-dependent manner, as measured by increased cleaved caspase 3/7 activity and Annexin V staining, respectively[1]. OH14 (100 μM; 1 h) requires the R38 residue in cFLIP to sensitize HeLa cells to TRAIL-induced apoptosis, while overexpression of wild-type, H7A, or K18I/R45A mutant cFLIP does not impair this sensitizing activity[1]. OH14 (100 μM; 1 h) significantly sensitizes MCF-7, BT474, and MDA-MB-231 breast cancer cell lines to TRAIL-induced cell death, with variable effects across other breast cancer subtypes[1]. OH14 (100 μM; 1 h) disrupts TRAIL-mediated recruitment of cFLIP to FADD in HeLa cells, as measured by loss of FRET signal between cFLIP-YFP and FADD-CFP[1]. OH14 (100 μM; 1 h) specifically disrupts TRAIL-mediated recruitment of cFLIP to the FADD complex in MCF-7 cells, while allowing procaspase-8 cleavage and activation[1]. OH14 (10 μM; 10 days) sensitizes MCF-7 breast cancer cells to TRAIL-induced reduction in colony formation, without affecting colony growth when administered alone[1]. OH14 (10 μM; 24 h) is non-toxic to HEK293 non-tumorigenic human embryonic kidney cells, either alone or in combination with TRAIL[1].
References:
[1]. Giancotti G, et al. The Discovery of Small Molecule Inhibitors of cFLIP that Sensitise Tumour Cells to TRAIL[J]. bioRxiv, 2024: 2024.04. 22.590574.