G9D-4 TFA is a G9a PROTAC degrader. G9D-4 TFA induces G9a degradation, reduces H3K9me2 levels, and prevents GLP interference via the CRBN ternary complex, proteasome and ubiquitin-like modification-dependent pathways. G9D-4 TFA exerts antiproliferative activity and induces Apoptosis in pancreatic cancer cells. G9D-4 TFA can be used for research on pancreatic cancer [1]. (Pink: EHMT2/G9a/KMT1C ligand; Blue: Cereblon ligand; Black: linker).
In Vitro, G9D-4 (0.008-20 μM; 0-24 h) TFA induces G9a degradation in PANC-1 and ASPC-1 cells, with DC50 values of 0.1 μM and 0.2 μM, respectively. It accelerates the degradation of G9a protein in PANC-1 cells without altering GLP protein levels[1]. G9D-4 (0.04-10 μM; 24 h) TFA reduces the level of H3K9me2 in PANC-1 cells[1]. G9D-4 (1 μM; 8 h) TFA induces G9a degradation in PANC-1 cells. This process requires the formation of a G9a-G9D-4 TFA-CRBN ternary complex and is dependent on the neddylation-proteasome pathway[1]. G9D-4 (72 h) TFA inhibits the cell growth of a panel of pancreatic cancer cell lines (KP-4, PANC-1, ASPC-1, HPAF-II, Panc10.05, SW1990, Panc08.13, Panc04.03, Panc05.04, and Panc02.03 cells), with IC50 values ranging from 12 to 32 μM, also inhibits the growth of 22Rv1 cells, with an IC50 of 9.9 μM[1]. G9D-4 (0.1-12.5 μM; 24 h) TFA induces apoptosis in PANC-1 cells, downregulates G9a and H3K9me2, and upregulates γH2AX and cleaved PARP[1]. G9D-4 (0-15 μM; 72 h) TFA enhances the inhibitory effect of MRTX1133 on cell proliferation of KRASG12D-mutant pancreatic cancer cell lines (ASPC-1 cells and KP-4 cells), and synergistically induces cell apoptosis[1]. G9D-4 (5-10 μM; 10−14 days) TFA significantly enhances the colony formation inhibitory activity of MRTX1133 in KP-4 cells, and exerts a synergistic inhibitory effect on long-term cell proliferation[1].
References:
[1]. Yunkai Shi, et al. Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer. J Med Chem. 2024 Jul 23.
In Vitro, G9D-4 (0.008-20 μM; 0-24 h) TFA induces G9a degradation in PANC-1 and ASPC-1 cells, with DC50 values of 0.1 μM and 0.2 μM, respectively. It accelerates the degradation of G9a protein in PANC-1 cells without altering GLP protein levels[1]. G9D-4 (0.04-10 μM; 24 h) TFA reduces the level of H3K9me2 in PANC-1 cells[1]. G9D-4 (1 μM; 8 h) TFA induces G9a degradation in PANC-1 cells. This process requires the formation of a G9a-G9D-4 TFA-CRBN ternary complex and is dependent on the neddylation-proteasome pathway[1]. G9D-4 (72 h) TFA inhibits the cell growth of a panel of pancreatic cancer cell lines (KP-4, PANC-1, ASPC-1, HPAF-II, Panc10.05, SW1990, Panc08.13, Panc04.03, Panc05.04, and Panc02.03 cells), with IC50 values ranging from 12 to 32 μM, also inhibits the growth of 22Rv1 cells, with an IC50 of 9.9 μM[1]. G9D-4 (0.1-12.5 μM; 24 h) TFA induces apoptosis in PANC-1 cells, downregulates G9a and H3K9me2, and upregulates γH2AX and cleaved PARP[1]. G9D-4 (0-15 μM; 72 h) TFA enhances the inhibitory effect of MRTX1133 on cell proliferation of KRASG12D-mutant pancreatic cancer cell lines (ASPC-1 cells and KP-4 cells), and synergistically induces cell apoptosis[1]. G9D-4 (5-10 μM; 10−14 days) TFA significantly enhances the colony formation inhibitory activity of MRTX1133 in KP-4 cells, and exerts a synergistic inhibitory effect on long-term cell proliferation[1].
References:
[1]. Yunkai Shi, et al. Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer. J Med Chem. 2024 Jul 23.