Structure–Activity Relationship Study of Indolin-5-yl-cyclopropanamine Derivatives as Selective Lysine Specific Demethylase 1 (LSD1) Inhibitors

LSD1 is identified as an essential
drug target, which is closely
correlated to the development of several tumor types. In this work,
on the basis of comprehensive analysis of the binding site of LSD1
and other FAD-dependent enzymes, a novel series of potent and selective
LSD1 inhibitors were designed by incorporation of privileged indoline
scaffold strategies. Representative compound 7e (LSD1;
IC50 = 24.43 nM, selectivity over LSD2 and MAOs of >200-
and 4000-fold) possessed selective antiproliferative activities against
MV-4-11 cell lines. Further study indicates that 7e could
activate CD86 expression (EC50 = 470 nM) and induce differentiation
of AML cell lines. More importantly, compound 7e demonstrated
an acceptable oral PK profile and good in vivo antitumor
efficacy with a T/C value of 30.89%
in an MV-4-11 xenograft mouse model. Collectively, this work provides
a promising lead compound for the development of novel LSD1 inhibitors
for the treatment of AML.