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 (12) validated by biochemical and biophysical
assays, we describe our efforts to develop acyclic scaffold-hops from
GSK-690 (1). A further scaffold modification to a (4-cyanophenyl)­glycinamide
(e.g., 29a) led to the development of compound 32, with a Kd value of 32 nM and
an EC50 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 1 and represents
a promising lead for further development.