1 research outputs found
Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1
Inhibition
of lysine specific demethylase 1 (LSD1) has been shown to induce the
differentiation of leukemia stem cells in acute myeloid leukemia (AML).
Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine
have entered clinical trials; however, the development of effective
reversible inhibitors has proved more challenging. Herein, we describe
our efforts to identify reversible inhibitors of LSD1 from a high
throughput screen and subsequent in silico modeling approaches. From
a single hit (<b>12</b>) validated by biochemical and biophysical
assays, we describe our efforts to develop acyclic scaffold-hops from
GSK-690 (<b>1</b>). A further scaffold modification to a (4-cyanophenyl)glycinamide
(e.g., <b>29a</b>) led to the development of compound <b>32</b>, with a <i>K</i><sub>d</sub> value of 32 nM and
an EC<sub>50</sub> value of 0.67 μM in a surrogate cellular
biomarker assay. Moreover, this derivative does not display the same
level of hERG liability as observed with <b>1</b> and represents
a promising lead for further development