1227195-11-0Relevant articles and documents
Toward the development of potent and selective bisubstrate inhibitors of protein arginine methyltransferases
Dowden, James,Hong, Wei,Parry, Richard V.,Pike, Richard A.,Ward, Stephen G.
, p. 2103 - 2105 (2010)
Prototype inhibitors of protein arginine methyltransferases (PRMTs) have been constructed by attaching guanidine functionality via a variable linker to non-reactive amine analogues of the cellular co-factor (S)-adenosyl methionine (AdoMet). Potent inhibition of PRMT1 (IC50 of ～3-6 μM) combined with weak inhibition of the lysine methyltransferase SET7 (～50% of activity at 100 μM) was observed for two such compounds.
Design, synthesis, and kinetic analysis of potent protein N-terminal methyltransferase 1 inhibitors
Zhang, Gang,Richardson, Stacie Lynn,Mao, Yunfei,Huang, Rong
, p. 4149 - 4154 (2015)
The protein N-terminal methyltransferase 1 (NTMT1) methylates the α-N-terminal amines of proteins. NTMT1 is upregulated in a variety of cancers and knockdown of NTMT1 results in cell mitotic defects. Therefore, NTMT1 inhibitors could be potential anticancer therapeutics. This study describes the design and synthesis of the first inhibitor targeting NTMT1. A novel bisubstrate analogue (NAM-TZ-SPKRIA) was shown to be a potent inhibitor (Ki = 0.20 μM) for NTMT1 and was selective versus protein lysine methyltransferase G9a and arginine methyltransferase 1. NAM-TZ-SPKRIA was found to exhibit a competitive inhibition pattern for both substrates, and mass spectrometry experiments revealed that the inhibitor substantially suppressed the methylation progression. Our results demonstrate the feasibility of using a triazole group to link an S-adenosyl-l-methionine analog with a peptide substrate to construct bisubstrate analogues as NTMT1 potent and selective inhibitors. This study lays a foundation to further discover small molecule NTMT1 inhibitors to interrogate its biological functions, and suggests a general strategy for the development of selective protein methyltransferase inhibitors. This journal is
NOVEL HISTONE METHYLTRANSFERASE INHIBITORS
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Page/Page column 30; 71-72, (2021/04/01)
The present invention relates to novel compounds of formula (I) as defined herein. The compounds are inhibitors of histone methyltransferases of the seven-beta-strand family, in particular of KMT9.
Design of a fluorescent ligand targeting the S-adenosylmethionine binding site of the histone methyltransferase MLL1
Luan, Yepeng,Blazer, Levi L.,Hu, Hao,Hajian, Taraneh,Zhang, Jing,Wu, Hong,Houliston, Scott,Arrowsmith, Cheryl H.,Vedadi, Masoud,Zheng, Yujun George
, p. 631 - 638 (2016/01/12)
The histone methyltransferase MLL1 has been linked to translocation-associated gene fusion in childhood leukemias and is an attractive drug target. High-throughput biochemical analysis of MLL1 methyltransferase activity requires the production of at least a trimeric complex of MLL1, RbBP5 and WDR5 to elicit robust activity. Production of trimeric and higher order MLL1 complexes in the quantities and reproducibility required for high-throughput screening presents a significant impediment to MLL1 drug discovery efforts. We present here a small molecule fluorescent ligand (FL-NAH, 6) that is able to bind to the S-adenosylmethionine (SAM) binding site of MLL1 in a manner independent of the associated complex members. We have used FL-NAH to develop a fluorescence polarization-based SAM displacement assay in a 384-well format targeting the MLL1 SET domain in the absence of associated complex members. FL-NAH competes with SAM and is displaced from the MLL1 SET domain by other SAM-binding site ligands with Kdisp values similar to the higher-order complexes, but is unaffected by the H3 peptide substrate. This assay enables screening for SAM-competitive MLL1 inhibitors without requiring the use of trimeric or higher order MLL1 complexes, significantly reducing screening time and cost.
