Table 3.
H3K9 lysine methyltransferase inhibitors in development for cancer therapies and associated mechanisms of action (18)
| Reference | Compound | KMT and methylation target | Selectivity | IC50 | Mechanism of action |
|---|---|---|---|---|---|
| Greiner (2005) (153) | Chaetocin | KMT1A, G9A H3K9me1/me2 | Low | 0.8 μM | Mixed disulfide linkages formed between cysteine residues of enzyme and inhibitor |
| Chang (2009) (154) | BIX-01338 | G9A, GLP, and other KMTs | Not selective | 5-15 μM | Unknown |
| Chang (2009) (154) | BIX-01294 | G9A and GLP, H3K9me2 | Selective | 1.7 μM | Binds to the substrate binding groove of the enzyme to prevent enzyme and substrate (SAH) interaction |
| Liu (2009) (155) | UNC0224 | G9A and GLP, H3K9me2 | Selective | 15-30 nM | Occupation of the G9A lysine binding channel by the 7-dimethylaminopropoxy group |
| Liu (2010) (156) | UNC0321 | G9A and GLP, H3K9me2 | Selective | 63 pM | Same as UNC0638 but with a longer ethoxyethyl chain instead of the 3-carbon chain of UNC0638. |
| Chang (2010) (157) | E72 | G9A and GLP | Selective | 100 nM | A lysine mimic added to the BIX-01294 structure to inhibit substrate binding |
| Vedadi (2011) (158) | UNC0638 | G9A and GLP, H3K9me1/me2 | Selective | 15-20 nM | Competition with the lysine substrate. This inhibitor occupies the substrate binding groove and does not interact with the SAM binding pocket |
| Liu (2013) (159) | UNC0642 | G9A and GLP, H3K9me1/me2 | Selective | < 2.5 nM | Same as UNC0638 but with optimized in vivo pharmacokinetic properties |
| Konze (2014) (160) | UNC0965 | G9A and GLP H3K9me1/me2 | Selective | 15-20 nM | A biotinylated derivative of UNC0638 |
| Yuan (2012) (161) | BRD4770 BRD9539 |
G9A, GLP, PRC2-EZH2, H3K9me2/me3 | Less selective | 6.3 nM | SAM-competitive inhibitor |
| Sweis (2014) (162) | A-366 | G9A and GLP, H3K9me1/me2 | Selective | 3.3-38 nM | Substrate-competitive inhibitor |
Abbreviations: GLP, G9A-like protein; IC50, half maximal inhibitory concentration; KMT, lysine methyltransferase; SAH, S-adenosylhomocysteine; SAM, S-adenosyl methionine.