Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening

Histone
methyltransferases are involved in various biological functions, and
these methylation regulating enzymes’ abnormal expression or
activity has been noted in several human cancers. Within this context,
SET domain-containing (lysine methyltransferase) 7 (SET7, also called
KMT7, SETD7, SET9) is of increasing significance due to its diverse
roles in biological functions and diseases, such as diabetes, cancers,
alopecia areata, atherosclerotic vascular disease, HIV, and HCV. In
this study, DC-S100, which was discovered by pharmacophore- and docking-based
virtual screening, was identified as the hit compound of SET7 inhibitor.
Structure–activity relationship (SAR) analysis was performed
on analogs of DC-S100 and according to the putative binding mode of
DC-S100, structure modifications were made to improve its activity.
Of note, compounds DC-S238 and DC-S239, with IC50 values
of 4.88 and 4.59 μM, respectively, displayed selectivity for
DNMT1, DOT1L, EZH2, NSD1, SETD8, and G9a. Taken together, DC-S238
and DC-S239 can serve as leads for further investigation as SET7 inhibitors
and the chemical toolkits for functional biology studies of SET7.