Steric structure–activity relationship of cyproheptadine derivatives as inhibitors of histone methyltransferase Set7/9

Structure–Activity Relationship Studies on (R)‐PFI‐2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7

“…The substrate in this study was ERα, and in vivo inhibition led to blocking of estrogen‐dependent breast cancer cell growth in MCF7 cells . A structure–activity relationship study was performed, however, none of the analogues proved to be more potent than cyproheptadine . Several SAM derivatives have also been reported to inhibit SETD7 methyltransferase activity; for instance, DAAM‐3 (IC 50 10 μ m ) and DC‐S239 (IC 50 4.59 μ m ) .…”

Recent Advances in Chemical Tools for the Regulation and Study of Protein Lysine Methyltransferases

“…Cyproheptadine inhibited the methylation‐mediated stabilization of ERα and the estrogen‐dependent growth of breast cancer MCF‐7 cells, so it has been proposed to be a candidate therapeutic agent for breast cancer. Further study of derivatives of cyproheptadine suggested that its characteristic butterfly‐like conformation with a bent tricyclic dibenzosuberene moiety and chair‐form piperidine ring is important for the inhibition of SETD7, but is less important for the serotonin receptor‐antagonistic activity . By further optimization, more potent inhibitor, 2‐hydroxycyproheptadine, has also been reported very recently…”

Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine

“…Cyproheptadine ( 1 ) consists of N ‐methylpiperidine and tricyclic dibenzosuberene moieties. Our previous study indicated the importance of the N ‐methyl group on the piperidine ring and a key role of the characteristic butterfly‐like conformation . Replacement of the N ‐methyl group with any other substituent examined resulted in decreased inhibitory activity.…”

“…Our previous study indicatedt he importance of the N-methyl group on the piperidiner ing and ak ey role of the characteristic butterfly-likec onformation. [27] Replacement of the N-methyl group with any other substituent examined resulted in decreased inhibitory activity.X -ray structural analysisc onfirmed that the space around the N-methyl group was quite restricted in the The histonem ethyltransferase SET7/9 methylates not only histone but also non-histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously,o ur group identified cyproheptadine, used clinically as as erotonin receptor antagonist and histamine receptor (H1) antagonist, as an ovel scaffold of the SET7/9 inhibitor.I nt his work, we focused on dibenzosuberene as as ubstructure of cyproheptadine and synthesized derivatives with various functional groups.A mongt hem, the compound bearing a2 -hydroxy group showedt he most potent ac-tivity.O nt he other hand, a3 -hydroxy group or another hydrophilic functional group such as acetamide decreased the activity.S tructurala nalysis clarifiedarationale for the improved potency only by tightly restricted location and type of the hydrophilic group.…”